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9624_9	Sheik & Sater Adaptation In October 2014 word spread on social media that Duncan Sheik and Steven Sater, who had previously worked together on the Tony Award-winning and commercially successful rock musical adaptation Spring Awakening, were in talks with Karam and Paparelli to adapt columbinus into a rock musical. As of February 2015 the only detail which has been released is the possibility that due to the subject matter's sensitive nature Sheik and Sater may instead fictionalize the two leads.
9624_10	Critical response When columbinus premiered in 2005 at the Round House Theatre, Peter Marks of The Washington Post called it "An ambitious examination of the suburbanization of evil, directed with a surefire sense of theatricality by PJ Paparelli." Marks noted that "The script, by a writing team headed by Paparelli... is heavily based on research. (Stephen Karam and Sean McNall are credited as co-writers.) The words of Harris and Klebold, as well as court records, statements of Columbine witnesses and interviews with high school students across the country are incorporated into the proceedings. Other conversations are invented."
9624_11	The Variety reviewer (of the Off-Broadway production) wrote: "While the first act overdoes the buildup, act two has Miller and Rogers manfully shouldering their complicated characters and delivering the goods on their tormented inner lives. Here, scribes Karam and Paparelli drop the universal material of teen angst garnered from interviews in favor of words drawn from the private diaries, emails and videotapes that go a long way in exploring the twisted thinking behind the shootings... the production is especially well served by the wall of sound created by Martin Desjardins to suggest the demonic thoughts ricocheting in the boys' brains as they bought guns, made bombs, dressed to kill and worked themselves into a homicidal frame of mind by obsessing on their grievances as social outcasts."
9624_12	The New York Times reviewer (of the Off-Broadway production) wrote: "Mr. Karam and Mr. Paparelli have captured authentic notes of adolescent anxiety and yearning in briskly drawn scenes set in and around the classroom, the gym and the cafeteria. The dialogue is occasionally enlivened by a sharp jab of wit ... Much of it is also depressing or disturbing. And when the focus shrinks to the actual killings, and the dialogue is drawn from the testimony of the survivors of the rampage, the play becomes more upsetting still... ultimately don't offer any illuminating new views of the tangle of psychological and cultural factors behind it (including, of course, the easy availability of guns)."
9624_13	Awards and nominations columbinus received Helen Hayes Award nominations including: The Charles MacArthur Award for Outstanding New Play or Musical Outstanding Resident Play Outstanding Director - Resident Play Outstanding Sound Design - Resident Play or Musical (Martin Desjardins) (for which it won) columbinus received two Lucille Lortel Award nominations, for Outstanding Director and Outstanding Sound Design (winner). See also Eric Harris and Dylan Klebold Columbine High School Massacre References External links Internet Off-Broadway Database 'columbinus', Dramatic Publishing 2005 plays Works about the Columbine High School massacre Plays by Stephen Karam
9625_0	Membrane potential (also transmembrane potential or membrane voltage) is the difference in electric potential between the interior and the exterior of a biological cell. For the exterior of the cell, typical values of membrane potential, normally given in units of millivolts and denoted as mV, range from –80 mV to –40 mV. All animal cells are surrounded by a membrane composed of a lipid bilayer with proteins embedded in it. The membrane serves as both an insulator and a diffusion barrier to the movement of ions. Transmembrane proteins, also known as ion transporter or ion pump proteins, actively push ions across the membrane and establish concentration gradients across the membrane, and ion channels allow ions to move across the membrane down those concentration gradients. Ion pumps and ion channels are electrically equivalent to a set of batteries and resistors inserted in the membrane, and therefore create a voltage between the two sides of the membrane.
9625_1	Almost all plasma membranes have an electrical potential across them, with the inside usually negative with respect to the outside. The membrane potential has two basic functions. First, it allows a cell to function as a battery, providing power to operate a variety of "molecular devices" embedded in the membrane. Second, in electrically excitable cells such as neurons and muscle cells, it is used for transmitting signals between different parts of a cell. Signals are generated by opening or closing of ion channels at one point in the membrane, producing a local change in the membrane potential. This change in the electric field can be quickly sensed by either adjacent or more distant ion channels in the membrane. Those ion channels can then open or close as a result of the potential change, reproducing the signal.
9625_2	In non-excitable cells, and in excitable cells in their baseline states, the membrane potential is held at a relatively stable value, called the resting potential. For neurons, typical values of the resting potential range from –80 to –70 millivolts; that is, the interior of a cell has a negative baseline voltage of a bit less than one-tenth of a volt. The opening and closing of ion channels can induce a departure from the resting potential. This is called a depolarization if the interior voltage becomes less negative (say from –70 mV to –60 mV), or a hyperpolarization if the interior voltage becomes more negative (say from –70 mV to –80 mV). In excitable cells, a sufficiently large depolarization can evoke an action potential, in which the membrane potential changes rapidly and significantly for a short time (on the order of 1 to 100 milliseconds), often reversing its polarity. Action potentials are generated by the activation of certain voltage-gated ion channels.
9625_3	In neurons, the factors that influence the membrane potential are diverse. They include numerous types of ion channels, some of which are chemically gated and some of which are voltage-gated. Because voltage-gated ion channels are controlled by the membrane potential, while the membrane potential itself is influenced by these same ion channels, feedback loops that allow for complex temporal dynamics arise, including oscillations and regenerative events such as action potentials.
9625_4	Physical basis The membrane potential in a cell derives ultimately from two factors: electrical force and diffusion. Electrical force arises from the mutual attraction between particles with opposite electrical charges (positive and negative) and the mutual repulsion between particles with the same type of charge (both positive or both negative). Diffusion arises from the statistical tendency of particles to redistribute from regions where they are highly concentrated to regions where the concentration is low. Voltage
9625_5	Voltage, which is synonymous with difference in electrical potential, is the ability to drive an electric current across a resistance. Indeed, the simplest definition of a voltage is given by Ohm's law: V=IR, where V is voltage, I is current and R is resistance. If a voltage source such as a battery is placed in an electrical circuit, the higher the voltage of the source the greater the amount of current that it will drive across the available resistance. The functional significance of voltage lies only in potential differences between two points in a circuit. The idea of a voltage at a single point is meaningless. It is conventional in electronics to assign a voltage of zero to some arbitrarily chosen element of the circuit, and then assign voltages for other elements measured relative to that zero point. There is no significance in which element is chosen as the zero point—the function of a circuit depends only on the differences not on voltages per se. However, in most cases and by
9625_6	convention, the zero level is most often assigned to the portion of a circuit that is in contact with ground.
9625_7	The same principle applies to voltage in cell biology. In electrically active tissue, the potential difference between any two points can be measured by inserting an electrode at each point, for example one inside and one outside the cell, and connecting both electrodes to the leads of what is in essence a specialized voltmeter. By convention, the zero potential value is assigned to the outside of the cell and the sign of the potential difference between the outside and the inside is determined by the potential of the inside relative to the outside zero.
9625_8	In mathematical terms, the definition of voltage begins with the concept of an electric field , a vector field assigning a magnitude and direction to each point in space. In many situations, the electric field is a conservative field, which means that it can be expressed as the gradient of a scalar function , that is, . This scalar field is referred to as the voltage distribution. Note that the definition allows for an arbitrary constant of integration—this is why absolute values of voltage are not meaningful. In general, electric fields can be treated as conservative only if magnetic fields do not significantly influence them, but this condition usually applies well to biological tissue.
9625_9	Because the electric field is the gradient of the voltage distribution, rapid changes in voltage within a small region imply a strong electric field; on the converse, if the voltage remains approximately the same over a large region, the electric fields in that region must be weak. A strong electric field, equivalent to a strong voltage gradient, implies that a strong force is exerted on any charged particles that lie within the region. Ions and the forces driving their motion
9625_10	Electrical signals within biological organisms are, in general, driven by ions. The most important cations for the action potential are sodium (Na+) and potassium (K+). Both of these are monovalent cations that carry a single positive charge. Action potentials can also involve calcium (Ca2+), which is a divalent cation that carries a double positive charge. The chloride anion (Cl−) plays a major role in the action potentials of some algae, but plays a negligible role in the action potentials of most animals.
9625_11	Ions cross the cell membrane under two influences: diffusion and electric fields. A simple example wherein two solutions—A and B—are separated by a porous barrier illustrates that diffusion will ensure that they will eventually mix into equal solutions. This mixing occurs because of the difference in their concentrations. The region with high concentration will diffuse out toward the region with low concentration. To extend the example, let solution A have 30 sodium ions and 30 chloride ions. Also, let solution B have only 20 sodium ions and 20 chloride ions. Assuming the barrier allows both types of ions to travel through it, then a steady state will be reached whereby both solutions have 25 sodium ions and 25 chloride ions. If, however, the porous barrier is selective to which ions are let through, then diffusion alone will not determine the resulting solution. Returning to the previous example, let's now construct a barrier that is permeable only to sodium ions. Now, only sodium is
9625_12	allowed to diffuse cross the barrier from its higher concentration in solution A to the lower concentration in solution B. This will result in a greater accumulation of sodium ions than chloride ions in solution B and a lesser number of sodium ions than chloride ions in solution A.
9625_13	This means that there is a net positive charge in solution B from the higher concentration of positively charged sodium ions than negatively charged chloride ions. Likewise, there is a net negative charge in solution A from the greater concentration of negative chloride ions than positive sodium ions. Since opposite charges attract and like charges repel, the ions are now also influenced by electrical fields as well as forces of diffusion. Therefore, positive sodium ions will be less likely to travel to the now-more-positive B solution and remain in the now-more-negative A solution. The point at which the forces of the electric fields completely counteract the force due to diffusion is called the equilibrium potential. At this point, the net flow of the specific ion (in this case sodium) is zero. Plasma membranes
9625_14	Every cell is enclosed in a plasma membrane, which has the structure of a lipid bilayer with many types of large molecules embedded in it. Because it is made of lipid molecules, the plasma membrane intrinsically has a high electrical resistivity, in other words a low intrinsic permeability to ions. However, some of the molecules embedded in the membrane are capable either of actively transporting ions from one side of the membrane to the other or of providing channels through which they can move.
9625_15	In electrical terminology, the plasma membrane functions as a combined resistor and capacitor. Resistance arises from the fact that the membrane impedes the movement of charges across it. Capacitance arises from the fact that the lipid bilayer is so thin that an accumulation of charged particles on one side gives rise to an electrical force that pulls oppositely charged particles toward the other side. The capacitance of the membrane is relatively unaffected by the molecules that are embedded in it, so it has a more or less invariant value estimated at about 2 μF/cm2 (the total capacitance of a patch of membrane is proportional to its area). The conductance of a pure lipid bilayer is so low, on the other hand, that in biological situations it is always dominated by the conductance of alternative pathways provided by embedded molecules. Thus, the capacitance of the membrane is more or less fixed, but the resistance is highly variable.
9625_16	The thickness of a plasma membrane is estimated to be about 7-8 nanometers. Because the membrane is so thin, it does not take a very large transmembrane voltage to create a strong electric field within it. Typical membrane potentials in animal cells are on the order of 100 millivolts (that is, one tenth of a volt), but calculations show that this generates an electric field close to the maximum that the membrane can sustain—it has been calculated that a voltage difference much larger than 200 millivolts could cause dielectric breakdown, that is, arcing across the membrane. Facilitated diffusion and transport
9625_17	The resistance of a pure lipid bilayer to the passage of ions across it is very high, but structures embedded in the membrane can greatly enhance ion movement, either actively or passively, via mechanisms called facilitated transport and facilitated diffusion. The two types of structure that play the largest roles are ion channels and ion pumps, both usually formed from assemblages of protein molecules. Ion channels provide passageways through which ions can move. In most cases, an ion channel is permeable only to specific types of ions (for example, sodium and potassium but not chloride or calcium), and sometimes the permeability varies depending on the direction of ion movement. Ion pumps, also known as ion transporters or carrier proteins, actively transport specific types of ions from one side of the membrane to the other, sometimes using energy derived from metabolic processes to do so. Ion pumps
9625_18	Ion pumps are integral membrane proteins that carry out active transport, i.e., use cellular energy (ATP) to "pump" the ions against their concentration gradient. Such ion pumps take in ions from one side of the membrane (decreasing its concentration there) and release them on the other side (increasing its concentration there). The ion pump most relevant to the action potential is the sodium–potassium pump, which transports three sodium ions out of the cell and two potassium ions in. As a consequence, the concentration of potassium ions K+ inside the neuron is roughly 20-fold larger than the outside concentration, whereas the sodium concentration outside is roughly ninefold larger than inside. In a similar manner, other ions have different concentrations inside and outside the neuron, such as calcium, chloride and magnesium.
9625_19	If the numbers of each type of ion were equal, the sodium–potassium pump would be electrically neutral, but, because of the three-for-two exchange, it gives a net movement of one positive charge from intracellular to extracellular for each cycle, thereby contributing to a positive voltage difference. The pump has three effects: (1) it makes the sodium concentration high in the extracellular space and low in the intracellular space; (2) it makes the potassium concentration high in the intracellular space and low in the extracellular space; (3) it gives the intracellular space a negative voltage with respect to the extracellular space.
9625_20	The sodium-potassium pump is relatively slow in operation. If a cell were initialized with equal concentrations of sodium and potassium everywhere, it would take hours for the pump to establish equilibrium. The pump operates constantly, but becomes progressively less efficient as the concentrations of sodium and potassium available for pumping are reduced. Ion pumps influence the action potential only by establishing the relative ratio of intracellular and extracellular ion concentrations. The action potential involves mainly the opening and closing of ion channels not ion pumps. If the ion pumps are turned off by removing their energy source, or by adding an inhibitor such as ouabain, the axon can still fire hundreds of thousands of action potentials before their amplitudes begin to decay significantly. In particular, ion pumps play no significant role in the repolarization of the membrane after an action potential.
9625_21	Another functionally important ion pump is the sodium-calcium exchanger. This pump operates in a conceptually similar way to the sodium-potassium pump, except that in each cycle it exchanges three Na+ from the extracellular space for one Ca++ from the intracellular space. Because the net flow of charge is inward, this pump runs "downhill", in effect, and therefore does not require any energy source except the membrane voltage. Its most important effect is to pump calcium outward—it also allows an inward flow of sodium, thereby counteracting the sodium-potassium pump, but, because overall sodium and potassium concentrations are much higher than calcium concentrations, this effect is relatively unimportant. The net result of the sodium-calcium exchanger is that in the resting state, intracellular calcium concentrations become very low. Ion channels
9625_22	Ion channels are integral membrane proteins with a pore through which ions can travel between extracellular space and cell interior. Most channels are specific (selective) for one ion; for example, most potassium channels are characterized by 1000:1 selectivity ratio for potassium over sodium, though potassium and sodium ions have the same charge and differ only slightly in their radius. The channel pore is typically so small that ions must pass through it in single-file order. Channel pores can be either open or closed for ion passage, although a number of channels demonstrate various sub-conductance levels. When a channel is open, ions permeate through the channel pore down the transmembrane concentration gradient for that particular ion. Rate of ionic flow through the channel, i.e. single-channel current amplitude, is determined by the maximum channel conductance and electrochemical driving force for that ion, which is the difference between the instantaneous value of the
9625_23	membrane potential and the value of the reversal potential.
9625_24	A channel may have several different states (corresponding to different conformations of the protein), but each such state is either open or closed. In general, closed states correspond either to a contraction of the pore—making it impassable to the ion—or to a separate part of the protein, stoppering the pore. For example, the voltage-dependent sodium channel undergoes inactivation, in which a portion of the protein swings into the pore, sealing it. This inactivation shuts off the sodium current and plays a critical role in the action potential.
9625_25	Ion channels can be classified by how they respond to their environment. For example, the ion channels involved in the action potential are voltage-sensitive channels; they open and close in response to the voltage across the membrane. Ligand-gated channels form another important class; these ion channels open and close in response to the binding of a ligand molecule, such as a neurotransmitter. Other ion channels open and close with mechanical forces. Still other ion channels—such as those of sensory neurons—open and close in response to other stimuli, such as light, temperature or pressure.
9625_26	Leakage channels Leakage channels are the simplest type of ion channel, in that their permeability is more or less constant. The types of leakage channels that have the greatest significance in neurons are potassium and chloride channels. Even these are not perfectly constant in their properties: First, most of them are voltage-dependent in the sense that they conduct better in one direction than the other (in other words, they are rectifiers); second, some of them are capable of being shut off by chemical ligands even though they do not require ligands in order to operate. Ligand-gated channels
9625_27	Ligand-gated ion channels are channels whose permeability is greatly increased when some type of chemical ligand binds to the protein structure. Animal cells contain hundreds, if not thousands, of types of these. A large subset function as neurotransmitter receptors—they occur at postsynaptic sites, and the chemical ligand that gates them is released by the presynaptic axon terminal. One example of this type is the AMPA receptor, a receptor for the neurotransmitter glutamate that when activated allows passage of sodium and potassium ions. Another example is the GABAA receptor, a receptor for the neurotransmitter GABA that when activated allows passage of chloride ions. Neurotransmitter receptors are activated by ligands that appear in the extracellular area, but there are other types of ligand-gated channels that are controlled by interactions on the intracellular side.
9625_28	Voltage-dependent channels Voltage-gated ion channels, also known as voltage dependent ion channels, are channels whose permeability is influenced by the membrane potential. They form another very large group, with each member having a particular ion selectivity and a particular voltage dependence. Many are also time-dependent—in other words, they do not respond immediately to a voltage change but only after a delay.
9625_29	One of the most important members of this group is a type of voltage-gated sodium channel that underlies action potentials—these are sometimes called Hodgkin-Huxley sodium channels because they were initially characterized by Alan Lloyd Hodgkin and Andrew Huxley in their Nobel Prize-winning studies of the physiology of the action potential. The channel is closed at the resting voltage level, but opens abruptly when the voltage exceeds a certain threshold, allowing a large influx of sodium ions that produces a very rapid change in the membrane potential. Recovery from an action potential is partly dependent on a type of voltage-gated potassium channel that is closed at the resting voltage level but opens as a consequence of the large voltage change produced during the action potential.
9625_30	Reversal potential The reversal potential (or equilibrium potential) of an ion is the value of transmembrane voltage at which diffusive and electrical forces counterbalance, so that there is no net ion flow across the membrane. This means that the transmembrane voltage exactly opposes the force of diffusion of the ion, such that the net current of the ion across the membrane is zero and unchanging. The reversal potential is important because it gives the voltage that acts on channels permeable to that ion—in other words, it gives the voltage that the ion concentration gradient generates when it acts as a battery. The equilibrium potential of a particular ion is usually designated by the notation Eion.The equilibrium potential for any ion can be calculated using the Nernst equation. For example, reversal potential for potassium ions will be as follows:
9625_31	where Eeq,K+ is the equilibrium potential for potassium, measured in volts R is the universal gas constant, equal to 8.314 joules·K−1·mol−1 T is the absolute temperature, measured in kelvins (= K = degrees Celsius + 273.15) z is the number of elementary charges of the ion in question involved in the reaction F is the Faraday constant, equal to 96,485 coulombs·mol−1 or J·V−1·mol−1 [K+]o is the extracellular concentration of potassium, measured in mol·m−3 or mmol·l−1 [K+]i is the intracellular concentration of potassium
9625_32	Even if two different ions have the same charge (i.e., K+ and Na+), they can still have very different equilibrium potentials, provided their outside and/or inside concentrations differ. Take, for example, the equilibrium potentials of potassium and sodium in neurons. The potassium equilibrium potential EK is −84 mV with 5 mM potassium outside and 140 mM inside. On the other hand, the sodium equilibrium potential, ENa, is approximately +66 mV with approximately 12 mM sodium inside and 140 mM outside.
9625_33	Changes to membrane potential during development A neuron's resting membrane potential actually changes during the development of an organism. In order for a neuron to eventually adopt its full adult function, its potential must be tightly regulated during development. As an organism progresses through development the resting membrane potential becomes more negative. Glial cells are also differentiating and proliferating as development progresses in the brain. The addition of these glial cells increases the organism's ability to regulate extracellular potassium. The drop in extracellular potassium can lead to a decrease in membrane potential of 35 mV.
9625_34	Cell excitability Cell excitability is the change in membrane potential that is necessary for cellular responses in various tissues. Cell excitability is a property that is induced during early embriogenesis. Excitability of a cell has also been defined as the ease with which a response may be triggered. The resting and threshold potentials forms the basis of cell excitability and these processes are fundamental for the generation of graded and action potentials.
9625_35	The most important regulators of cell excitability are the extracellular electrolyte concentrations (i.e. Na+, K+, Ca2+, Cl−, Mg2+) and associated proteins. Important proteins that regulate cell excitability are voltage-gated ion channels, ion transporters (e.g. Na+/K+-ATPase, magnesium transporters, acid–base transporters), membrane receptors and hyperpolarization-activated cyclic-nucleotide-gated channels. For example, potassium channels and calcium-sensing receptors are important regulators of excitability in neurons, cardiac myocytes and many other excitable cells like astrocytes. Calcium ion is also the most important second messenger in excitable cell signaling. Activation of synaptic receptors initiates long-lasting changes in neuronal excitability. Thyroid, adrenal and other hormones also regulate cell excitability, for example, progesterone and estrogen modulate myometrial smooth muscle cell excitability.
9625_36	Many cell types are considered to have an excitable membrane. Excitable cells are neurons, myocytes (cardiac, skeletal, smooth), vascular endothelial cells, pericytes, juxtaglomerular cells, interstitial cells of Cajal, many types of epithelial cells (e.g. beta cells, alpha cells, delta cells, enteroendocrine cells, pulmonary neuroendocrine cells, pinealocytes), glial cells (e.g. astrocytes), mechanoreceptor cells (e.g. hair cells and Merkel cells), chemoreceptor cells (e.g. glomus cells, taste receptors), some plant cells and possibly immune cells. Astrocytes display a form of non-electrical excitability based on intracellular calcium variations related to the expression of several receptors through which they can detect the synaptic signal. In neurons, there are different membrane properties in some portions of the cell, for example, dendritic excitability endows neurons with the capacity for coincidence detection of spatially separated inputs. Equivalent circuit
9625_37	Electrophysiologists model the effects of ionic concentration differences, ion channels, and membrane capacitance in terms of an equivalent circuit, which is intended to represent the electrical properties of a small patch of membrane. The equivalent circuit consists of a capacitor in parallel with four pathways each consisting of a battery in series with a variable conductance. The capacitance is determined by the properties of the lipid bilayer, and is taken to be fixed. Each of the four parallel pathways comes from one of the principal ions, sodium, potassium, chloride, and calcium. The voltage of each ionic pathway is determined by the concentrations of the ion on each side of the membrane; see the Reversal potential section above. The conductance of each ionic pathway at any point in time is determined by the states of all the ion channels that are potentially permeable to that ion, including leakage channels, ligand-gated channels, and voltage-gated ion channels.
9625_38	For fixed ion concentrations and fixed values of ion channel conductance, the equivalent circuit can be further reduced, using the Goldman equation as described below, to a circuit containing a capacitance in parallel with a battery and conductance. In electrical terms, this is a type of RC circuit (resistance-capacitance circuit), and its electrical properties are very simple. Starting from any initial state, the current flowing across either the conductance or the capacitance decays with an exponential time course, with a time constant of , where is the capacitance of the membrane patch, and is the net resistance. For realistic situations, the time constant usually lies in the 1—100 millisecond range. In most cases, changes in the conductance of ion channels occur on a faster time scale, so an RC circuit is not a good approximation; however, the differential equation used to model a membrane patch is commonly a modified version of the RC circuit equation.
9625_39	Resting potential When the membrane potential of a cell goes for a long period of time without changing significantly, it is referred to as a resting potential or resting voltage. This term is used for the membrane potential of non-excitable cells, but also for the membrane potential of excitable cells in the absence of excitation. In excitable cells, the other possible states are graded membrane potentials (of variable amplitude), and action potentials, which are large, all-or-nothing rises in membrane potential that usually follow a fixed time course. Excitable cells include neurons, muscle cells, and some secretory cells in glands. Even in other types of cells, however, the membrane voltage can undergo changes in response to environmental or intracellular stimuli. For example, depolarization of the plasma membrane appears to be an important step in programmed cell death.
9625_40	The interactions that generate the resting potential are modeled by the Goldman equation. This is similar in form to the Nernst equation shown above, in that it is based on the charges of the ions in question, as well as the difference between their inside and outside concentrations. However, it also takes into consideration the relative permeability of the plasma membrane to each ion in question. The three ions that appear in this equation are potassium (K+), sodium (Na+), and chloride (Cl−). Calcium is omitted, but can be added to deal with situations in which it plays a significant role. Being an anion, the chloride terms are treated differently from the cation terms; the intracellular concentration is in the numerator, and the extracellular concentration in the denominator, which is reversed from the cation terms. Pi stands for the relative permeability of the ion type i.
9625_41	In essence, the Goldman formula expresses the membrane potential as a weighted average of the reversal potentials for the individual ion types, weighted by permeability. (Although the membrane potential changes about 100 mV during an action potential, the concentrations of ions inside and outside the cell do not change significantly. They remain close to their respective concentrations when then membrane is at resting potential.) In most animal cells, the permeability to potassium is much higher in the resting state than the permeability to sodium. As a consequence, the resting potential is usually close to the potassium reversal potential. The permeability to chloride can be high enough to be significant, but, unlike the other ions, chloride is not actively pumped, and therefore equilibrates at a reversal potential very close to the resting potential determined by the other ions.
9625_42	Values of resting membrane potential in most animal cells usually vary between the potassium reversal potential (usually around -80 mV) and around -40 mV. The resting potential in excitable cells (capable of producing action potentials) is usually near -60 mV—more depolarized voltages would lead to spontaneous generation of action potentials. Immature or undifferentiated cells show highly variable values of resting voltage, usually significantly more positive than in differentiated cells. In such cells, the resting potential value correlates with the degree of differentiation: undifferentiated cells in some cases may not show any transmembrane voltage difference at all.
9625_43	Maintenance of the resting potential can be metabolically costly for a cell because of its requirement for active pumping of ions to counteract losses due to leakage channels. The cost is highest when the cell function requires an especially depolarized value of membrane voltage. For example, the resting potential in daylight-adapted blowfly (Calliphora vicina) photoreceptors can be as high as -30 mV. This elevated membrane potential allows the cells to respond very rapidly to visual inputs; the cost is that maintenance of the resting potential may consume more than 20% of overall cellular ATP.
9625_44	On the other hand, the high resting potential in undifferentiated cells does not necessarily incur a high metabolic cost. This apparent paradox is resolved by examination of the origin of that resting potential. Little-differentiated cells are characterized by extremely high input resistance, which implies that few leakage channels are present at this stage of cell life. As an apparent result, potassium permeability becomes similar to that for sodium ions, which places resting potential in-between the reversal potentials for sodium and potassium as discussed above. The reduced leakage currents also mean there is little need for active pumping in order to compensate, therefore low metabolic cost.
9625_45	Graded potentials As explained above, the potential at any point in a cell's membrane is determined by the ion concentration differences between the intracellular and extracellular areas, and by the permeability of the membrane to each type of ion. The ion concentrations do not normally change very quickly (with the exception of Ca2+, where the baseline intracellular concentration is so low that even a small influx may increase it by orders of magnitude), but the permeabilities of the ions can change in a fraction of a millisecond, as a result of activation of ligand-gated ion channels. The change in membrane potential can be either large or small, depending on how many ion channels are activated and what type they are, and can be either long or short, depending on the lengths of time that the channels remain open. Changes of this type are referred to as graded potentials, in contrast to action potentials, which have a fixed amplitude and time course.
9625_46	As can be derived from the Goldman equation shown above, the effect of increasing the permeability of a membrane to a particular type of ion shifts the membrane potential toward the reversal potential for that ion. Thus, opening Na+ channels shifts the membrane potential toward the Na+ reversal potential, which is usually around +100 mV. Likewise, opening K+ channels shifts the membrane potential toward about –90 mV, and opening Cl− channels shifts it toward about –70 mV (resting potential of most membranes). Thus, Na+ channels shift the membrane potential in a positive direction, K+ channels shift it in a negative direction (except when the membrane is hyperpolarized to a value more negative than the K+ reversal potential), and Cl− channels tend to shift it towards the resting potential.
9625_47	Graded membrane potentials are particularly important in neurons, where they are produced by synapses—a temporary change in membrane potential produced by activation of a synapse by a single graded or action potential is called a postsynaptic potential. Neurotransmitters that act to open Na+ channels typically cause the membrane potential to become more positive, while neurotransmitters that activate K+ channels typically cause it to become more negative; those that inhibit these channels tend to have the opposite effect.
9625_48	Whether a postsynaptic potential is considered excitatory or inhibitory depends on the reversal potential for the ions of that current, and the threshold for the cell to fire an action potential (around –50mV). A postsynaptic current with a reversal potential above threshold, such as a typical Na+ current, is considered excitatory. A current with a reversal potential below threshold, such as a typical K+ current, is considered inhibitory. A current with a reversal potential above the resting potential, but below threshold, will not by itself elicit action potentials, but will produce subthreshold membrane potential oscillations. Thus, neurotransmitters that act to open Na+ channels produce excitatory postsynaptic potentials, or EPSPs, whereas neurotransmitters that act to open K+ or Cl− channels typically produce inhibitory postsynaptic potentials, or IPSPs. When multiple types of channels are open within the same time period, their postsynaptic potentials summate (are added
9625_49	together).
9625_50	Other values From the viewpoint of biophysics, the resting membrane potential is merely the membrane potential that results from the membrane permeabilities that predominate when the cell is resting. The above equation of weighted averages always applies, but the following approach may be more easily visualized. At any given moment, there are two factors for an ion that determine how much influence that ion will have over the membrane potential of a cell: That ion's driving force That ion's permeability If the driving force is high, then the ion is being "pushed" across the membrane. If the permeability is high, it will be easier for the ion to diffuse across the membrane.
9625_51	Driving force is the net electrical force available to move that ion across the membrane. It is calculated as the difference between the voltage that the ion "wants" to be at (its equilibrium potential) and the actual membrane potential (Em). So, in formal terms, the driving force for an ion = Em - Eion For example, at our earlier calculated resting potential of −73 mV, the driving force on potassium is 7 mV : (−73 mV) − (−80 mV) = 7 mV. The driving force on sodium would be (−73 mV) − (60 mV) = −133 mV. Permeability is a measure of how easily an ion can cross the membrane. It is normally measured as the (electrical) conductance and the unit, siemens, corresponds to 1 C·s−1·V−1, that is one coulomb per second per volt of potential.
9625_52	So, in a resting membrane, while the driving force for potassium is low, its permeability is very high. Sodium has a huge driving force but almost no resting permeability. In this case, potassium carries about 20 times more current than sodium, and thus has 20 times more influence over Em than does sodium. However, consider another case—the peak of the action potential. Here, permeability to Na is high and K permeability is relatively low. Thus, the membrane moves to near ENa and far from EK.
9625_53	The more ions are permeant the more complicated it becomes to predict the membrane potential. However, this can be done using the Goldman-Hodgkin-Katz equation or the weighted means equation. By plugging in the concentration gradients and the permeabilities of the ions at any instant in time, one can determine the membrane potential at that moment. What the GHK equations means is that, at any time, the value of the membrane potential will be a weighted average of the equilibrium potentials of all permeant ions. The "weighting" is the ions relative permeability across the membrane. Effects and implications While cells expend energy to transport ions and establish a transmembrane potential, they use this potential in turn to transport other ions and metabolites such as sugar. The transmembrane potential of the mitochondria drives the production of ATP, which is the common currency of biological energy.
9625_54	Cells may draw on the energy they store in the resting potential to drive action potentials or other forms of excitation. These changes in the membrane potential enable communication with other cells (as with action potentials) or initiate changes inside the cell, which happens in an egg when it is fertilized by a sperm. In neuronal cells, an action potential begins with a rush of sodium ions into the cell through sodium channels, resulting in depolarization, while recovery involves an outward rush of potassium through potassium channels. Both of these fluxes occur by passive diffusion. See also Bioelectrochemistry Electrochemical potential Goldman equation Membrane biophysics Microelectrode array Saltatory conduction Surface potential Gibbs–Donnan effect Synaptic potential Notes References
9625_55	Further reading Alberts et al. Molecular Biology of the Cell. Garland Publishing; 4th Bk&Cdr edition (March, 2002). . Undergraduate level. Guyton, Arthur C., John E. Hall. Textbook of medical physiology. W.B. Saunders Company; 10th edition (August 15, 2000). . Undergraduate level. Hille, B. Ionic Channel of Excitable Membranes Sinauer Associates, Sunderland, MA, USA; 1st Edition, 1984. Nicholls, J.G., Martin, A.R. and Wallace, B.G. From Neuron to Brain Sinauer Associates, Inc. Sunderland, MA, USA 3rd Edition, 1992. Ove-Sten Knudsen. Biological Membranes: Theory of Transport, Potentials and Electric Impulses. Cambridge University Press (September 26, 2002). . Graduate level. National Medical Series for Independent Study. Physiology. Lippincott Williams & Wilkins. Philadelphia, PA, USA 4th Edition, 2001.
9625_56	External links Functions of the Cell Membrane Nernst/Goldman Equation Simulator Nernst Equation Calculator Goldman-Hodgkin-Katz Equation Calculator Electrochemical Driving Force Calculator The Origin of the Resting Membrane Potential - Online interactive tutorial (Flash) Cell communication Cell signaling Cellular processes Cellular neuroscience Electrochemistry Electrophysiology Membrane biology
9626_0	Maria Karolina Zofia Felicja Leszczyńska (; ; 23 June 1703 – 24 June 1768), also known as Marie Leczinska, was Queen of France as the wife of King Louis XV from their marriage on 4 September 1725 until her death in 1768. The daughter of King Stanislaus I of Poland and Catherine Opalińska, her 42-year service was the longest of any queen in French history. A devout Roman Catholic throughout her life, Marie was popular among the French people for her generosity and introduced many Polish customs to the royal court at Versailles. She was the grandmother of Louis XVI, Louis XVIII and Charles X of France. Early life Maria Karolina Zofia Felicja Leszczyńska (Wieniawa) was the second daughter of Stanislaus I Leszczyński and his wife, Catherine Opalińska. She had an elder sister, Anna Leszczyńska, who died of pneumonia in 1717.
9626_1	Maria's early life was troubled by her father's political misfortune. Ironically, the hopeless political career of King Stanislaus was eventually the reason why his daughter Maria was chosen as the bride of King Louis XV of France. Devoid of political connections, his daughter was viewed by the French as being free from the burden of international alliances.
9626_2	She was born in Trzebnica in Lower Silesia, the year before her father was made King of Poland by Charles XII of Sweden, who had invaded the country in 1704. In 1709, her father was deposed when the Swedish army lost the military upper hand in Poland, and the family was granted refuge by Charles XII in the Swedish city of Kristianstad in Scania. During the escape, Marie was separated from the rest of her family; she was later found with her nurse hiding in a crib in a stable, although another version claims it was actually a cave in an old mineshaft. In Sweden, the family was welcomed by the queen dowager Hedwig Eleonora of Holstein-Gottorp and became popular members of society life on the estates of the nobility around Kristianstad. In 1712, they made an official visit to Medevi, the spa of the Queen Dowager. During this period in her life, Marie began speaking Swedish with a Scanian accent. As Queen of France, she was known to welcome Swedish ambassadors to France with the phrase
9626_3	"Welcome, Dearest Heart!" in Swedish.
9626_4	In 1714, Charles XII gave them permission to live in his fiefdom of Zweibrücken in the Holy Roman Empire, where they were supported by the income of Zweibrücken: they lived there until the death of Charles XII in 1718. Zweibrücken then passed to a cousin of his. These lands were parallel to the confiscated Polish properties of Stanislaus. Stanislaus appealed to the Regent of France, the Duke of Orléans, and the Duke of Lorraine for help, with the Queen of Sweden acting as his mediator. In 1718, with the support of the Duke of Lorraine, the family was allowed to settle in Wissembourg in the province of Alsace, which had been annexed by France, a place suggested by Philippe II, Duke of Orléans, a nephew of Louis XIV and Regent of the Kingdom of France during Louis XV's minority. The family lived a modest life in a large town house at the expense of the French Regent.
9626_5	Their lifestyle in Wissembourg was regarded as very below standard for a royal at that time; they lived in a small house, and could not pay the salary of their small retinue from which a few "served as an apology for a guard of honour", and the jewels of the former Queen Catherine were reportedly held as security by a moneylender. While her mother Catherine and grandmother Anna Leszczyńska reportedly suffered from a certain degree of bitterness over their exile and loss of position which worsened their relationship with Stanislaus, whom they occasionally blamed for their exile, Marie was close to her father and spent a lot of time conversing with him, though she was evidently of a more rational nature as she "possessed the gift of suffering in silence and of never wearying others with her troubles" and was said to have developed "a profound and intense piety", which gave "to her youthful mind the maturity of a woman who no longer demands happiness". Marriage Early negotiations
9626_6	Marie was not described as a beauty; instead her characteristics in the marriage market were stated as those of being pleasant, well-educated, and graceful in manner and movement. In 1720, she was suggested as a bride to Louis Henri de Bourbon, Prince of Condé (who preferred to be known as the Duke of Bourbon, rather than Prince of Condé), but her intended mother-in-law Louise Françoise de Bourbon refused to give her consent. The cavalry regiment provided by the Regent for the protection of the family included the officer Marquis de Courtanvaux, who fell in love with Marie and asked the Regent to be created a duke in order to ask for her hand; but when the Regent refused, the marriage became impossible because of his lack of rank. Louis George, Margrave of Baden-Baden as well as the third Prince of Baden were suggested, but these negotiations fell through because of her insufficient dowry. Stanislaus unsuccessfully tried to arrange a marriage for her with the Count of Charolais,
9626_7	brother of the Duke of Bourbon. In 1724, she was suggested by Count d'Argensson as a bride for the new Duke of Orléans, but her intended mother-in-law Françoise Marie de Bourbon wished for a dynastic match with political advantage.
9626_8	In 1723, the Duke of Bourbon had become the Regent of France during the minority of Louis XV. The Regent was highly dominated by his lover, Madame de Prie. There were long-ongoing negotiations of a marriage between Marie and the now widowed Duke of Bourbon: Madame de Prie favored the match, as she did not perceive the reputedly unattractive Marie as a threat to her. The marriage negotiations, however, were soon overshadowed when a marriage for King Louis XV was given priority. That same year, the young king fell ill and, fearing the consequences of the unmarried King dying without an heir, the Duc suggested getting the young King married as soon as possible. Louis XV was already engaged to Infanta Mariana Victoria of Spain, who had been brought to France as his future wife some years earlier and was referred to as the Infanta-Queen. However, the Infanta was still a child, and could not be expected to conceive for several years; while Louis XV, being fifteen, had already hit puberty.
9626_9	After Louis fell seriously ill, there was a great fear that he would die before he had time to have an heir to the throne. Should that happen, the throne would pass to the Orléans line. This was an undesirable prospect for the Duke of Bourbon, who himself would in fact have preferred that the throne should pass to the Spanish line rather than to the Orléans line. The engagement between Louis XV and the Spanish Infanta was broken, and the latter was sent back to Spain, much to the chagrin of the Spanish. The Duke of Bourbon and Madame de Prie began negotiations for the immediate marriage of the King to Marie.
9626_10	Negotiations for marriage to the King
9626_11	Marie was on a list of 99 eligible European princesses to marry the young King. She was not the first choice on the list. She had been placed there initially because she was a Catholic princess and therefore fulfilled the minimum criteria, but was removed early on when the list was reduced from 99 to 17 for being too poor. However, when the list of 17 was further reduced to four, the preferred choices presented numerous problems. Anne and Amelia of Great Britain, who were considered with the understanding that they would convert to the Catholic faith upon marriage, were favored by the Duke of Bourbon and Madame de Prie because it was supported by their political financiers, the firm of Paris Brothers Joseph Paris Duverney. Cardinal Fleury easily prevented the British match because of religious reasons. The last two were the sisters of the Duke of Bourbon, Henriette-Louise and Therese-Alexandrine, whom the King himself refused to marry because of the disapproval of Cardinal Fleury.
9626_12	Cardinal Fleury himself favored a match with Princess Charlotte of Hesse-Rheinfels-Rotenburg, which was supported by the maternal grandfather of Louis XV, The King of Sardinia through his spy the Princess of Carignan, Maria Vittoria of Savoy.
9626_13	In these complicated disputes over the choice of a royal marriage partner, Marie Leszczyńska eventually emerged as a choice acceptable to both the party of the Duke of Bourbon and Madame de Prie, as well as the party of Cardinal Fleury, mainly because she was politically uncontroversial and lacked any of the alliances which could harm either party. At this point, there were already negotiations of marriage between Marie and the Duke of Bourbon. The Duke of d'Argensson had already left a favorable report of her, and the groundwork had been done. Cardinal Fleury accepted the choice as Marie posed no threat to him because of her lack of connections, while the Duke of Bourbon and Madame de Prie, precisely because she lacked any personal power base, expected her to be indebted to them for her position. Marie was, finally, chosen because she was a healthy adult Catholic princess ready to procreate immediately after the wedding. Reportedly, Madame de Prie had a flattering portrait painted of
9626_14	Marie, in which she was deliberately made to look like the King's favorite portrait of his mother, and when he was shown it, he was impressed and exclaimed: "She is the loveliest of them all!" and became enthusiastic of the match, an episode which attracted some attention.
9626_15	The formal proposal was made on 2 April 1725. The announcement of the wedding was not received well at the royal court. Marie's father Stanislaus had been a monarch for only a short time and she was thought to be a poor choice of inferior status not worthy of being queen of France.
9626_16	The Dowager Duchess of Lorraine, sister of the former Duke of Orléans, was also insulted that her own daughter Elisabeth-Therese had not been chosen. The nobility and the court looked upon the future queen as an upstart intruder, the ministers as a cause to diplomatic trouble with Spain and Russia, whose princesses had been refused in favor of Marie, and the general public was also reportedly initially dissatisfied with the fact that France would gain "from this marriage neither glory nor honor, riches nor alliances." There were rumors before the wedding that the bride was ugly, epileptic and sterile. The 6 May 1725, Marie was forced to undergo a medical examination, which ruled out epilepsy and also gave reassuring reports about her menstruation and ability to procreate. In the marriage contract, the same terms were given to her as were previously given to the Spanish Infanta, and she was thus guaranteed fifty thousand crowns for rings and jewelry, two hundred and fifty thousand
9626_17	crowns upon her wedding, and the further guarantee of an annual widow allowance of twenty thousand crowns.
9626_18	Private relationship to Louis XV The marriage by proxy took place on 15 August 1725 in the Cathedral of Strasbourg, Louis XV represented by his cousin the Duke of Orléans, Louis le Pieux. Upon her marriage, Maria's Polish name was modified into French as Marie. Despite her surname being difficult to spell or to pronounce for the French, it was still commonly used by commoners. She was escorted on her way by Mademoiselle de Clermont, seven ladies-in-waiting, two maids-of-honour, numerous equerries and pages in a long train of coaches; however, she was not welcomed by triumphal entries, diplomatic greetings or the other official celebrations, as was normally the custom upon the arrival of a foreign princess upon a royal marriage. Marie made a good impression upon the public from the beginning, such as when she handed out largesse on her way to her wedding in Fontainebleau.
9626_19	Louis and Marie first met on the eve of their wedding, which took place on 5 September 1725 at the Château de Fontainebleau. Marie was twenty-two years old and Louis fifteen. The young couple was reported to have fallen in love at first sight. The relationship between Marie and Louis was initially described as a happy one, and for the first eight years of the marriage, Louis XV was faithful to her. Louis XV had been very impatient to marry her, was reportedly flattered to have a twenty two-year old wife at his age and refused to allow any criticism of her appearance. In August 1727, Marie gave birth to her first children, twins named Louise Élisabeth and Anne Henriette at the Palace of Versailles. The King was reportedly delighted, stating that after it had been said that he could not be a father, he had suddenly become the father of two. Cardinal Fleury, however, was much more displeased, and decided that until the Queen had given birth to a son, she would not be allowed to accompany
9626_20	the King on his trips but stay at Versailles. A year later, another daughter, Marie Louise, was born, much to the disappointment of the King. The awaited dauphin, Louis, was born on 4 September 1729 to the immense relief of the country, whose royal family had a history of failing to establish a secure male line of succession. In all, Marie had 10 live children, seven of whom survived to adulthood. Her children all regarded her as a role model of virtue, particularly the daughters, though Marie herself reportedly was not noted to show much affection toward them, being phlegmatic in her nature.
9626_21	Though not regarded as ugly, Marie was seen as plain with not much more than her fresh and healthy complexion in her favor; this faded due to her many pregnancies, but her piety prevented her from consenting to indulge in vanity in order make herself attractive. In her behavior she was described as incurably shy and timid of her husband: she considered it her duty to show him grateful reverence and was not able to relax enough to entertain him or flirt with him. Once, for example, she could find no other way to entertain him than to suggest him to kill the flies in the window panes. Louis XV, who suffered from restlessness and needed to be entertained, eventually became more inclined to listen when Marie was unfavorably compared to other women, and Cardinal Fleury, who wished to prevent Marie from eventually getting any influence over the King, favored the idea of the King taking a mistress as long as she was apolitical.
9626_22	Louis XV eventually became a notorious womanizer. In 1733, he entered into his first infidelity with Louise Julie de Mailly; until 1737, this relationship was not official, and she was known at court as the Fair Unknown. These years, Marie unsuccessfully tried to figure out who the mistress was and did display her displeasure over the state of affairs, but the adultery had the support of Cardinal Fleury because de Mailly was not interested in politics, and after the first years of the king's adultery, Marie became resigned to it. After the difficult birth of Princess Louise in 1737, which nearly took her life, Marie was advised by the doctors that another pregnancy may end her life, and from 1738, she refused Louis's entrance to her bedroom.
9626_23	In parallel with this, Louise Julie de Mailly was officially recognized as the King's royal mistress and favorite at court, and the relationship between the King and Queen discontinued in all but name, though they continued to perform their ceremonial roles side by side. The King paid only purely ceremonial visits to her rooms and no longer participated in her card games. The court, wary of her loss of the King's affection, only attended to her when court representation required.
9626_24	Louise Julie de Mailly was followed by Pauline Félicité de Mailly in 1739, Marie Anne de Mailly in 1742 and Diane Adélaïde de Mailly also in 1742. During the serious illness of Louis XV in Metz in August 1744, when he was believed to be dying, Marie was given his permission to join him. She was cheered by the supporting public along her journey, but when she arrived, he no longer wished to see her. She and the clergy supported the idea of the King exiling his mistress Marie Anne de Mailly including her sister, and the idea that the King should make a public regret for his adultery, but this did not improve their marriage.
9626_25	Madame de Pompadour was presented at court in 1745 and was given such an important and influential position at court until her death in 1764 that she somewhat eclipsed the Queen. The lovers of Louis were often given positions in the court of Marie in order for them to have a permanent access and official excuse to remain at court, which placed Marie in a difficult position. She regarded the first official mistress Louise Julie de Mailly as the most hurtful because she was the first one, however, she disliked Marie Anne de Mailly on a more personal level because Marie Anne was haughty and insolent. In contrast to the other official mistresses, Marie had a moderately friendly and cordial relationship to Madame de Pompadour, who always treated the Queen with deference and respect, though Marie did, unsuccessfully, oppose Pompadour's appointment as a lady-in-waiting in 1756. In contrast, Marie herself seems never to have had extramarital relations. Queen of France
9626_26	Political role Queen Marie never managed to develop political influence. After her marriage, her appointed court consisted of a great number of followers of the Duke of Bourbon, among them Madame de Prie, the Duchess de Béthune, and the Marquise de Matignon, who, among her twelve ladies-in-waiting or dame du palais, the Duke's own sister, Marie Anne de Bourbon, became her Surintendante de la Maison de la Reine and Paris de Verney was appointed as her secretary. Cardinal de Fleury, who had been Louis's tutor, was appointed her grand almoner.
9626_27	Marie had been given advice by her father to always loyally stand by the Duke of Bourbon, to whom she owed her marriage and position, and it was a favor to the Duke that Marie made her first attempt to interfere in politics. On 17 December 1725 the Duke of Bourbon, Madame de Prie and Paris de Verney attempted to banish Cardinal de Fleury through a plot. On their instruction, the Queen called on the King to come to her chambers, where the Duke de Bourbon was present. The doors were locked to ensure secrecy and the Duke presented the King with a report from their ambassador in Rome which blamed Fleury for the French failure in a dispute with the Pope. Bourbon asked the King if they should write a reply, which the King refused without the presence of Fleury. Meanwhile, Cardinal Fleury learned of the plot to discredit him and left the palace. The Duke and de Prie planned to use the absence of Fleury to have him confined to an abbey, and gave Marie the task of informing Louis XV that the
9626_28	absent Fleury wished to enter an Abbey and leave his position at court.
9626_29	This led to a crisis when the King gave Bourbon the choice to either expel Madame de Prie and Paris de Verney or be removed from his post of prime minister. This incident led to Cardinal Fleury categorizing Queen Marie as his opponent, and his decision to oust the ministry of the Duke of Bourbon. Cardinal Fleury warned the King that no woman should be allowed to participate in state affairs and that listening to women's advises would lead to disaster.
9626_30	In June 1726, Fleury convinced the King to deprive the Duke of Bourbon of his ministry. Madame de Prie immediately enlisted the Queen to speak to the King in favor of Bourbon. She protested but agreed and reportedly spoke passionately about the affair to the King, but she was unable to succeed as the King reacted very negatively to her attempt to interfere in politics after the preparation from Fleury that women should not be allowed to participate in state affairs. The day following the fall of the Duke de Bourbon's ministry, Louis XV stated to Queen Marie that he demanded of her to let herself be directed by Cardinal Fleury in the future with the words: "I beg, Madame, and, if necessary, I order you to place credence in everything that the former Archbishop of Frejus tells you on my behalf, as though he were I – Louis".
9626_31	Marie's attempt to participate in state affairs during the events of 1726 resulted in a crisis in her relationship with Louis XV, and she sought advice on how to behave from the Princess of Carignano, whom unbeknownst to her was a spy in service of Savoy. The princess' advice was that as Queen of France, it was Marie's duty not to involve herself in political intrigues and plots, but to act as an example of virtue and piety; a role model of a "Catholic consort of the Most Christian King". Queen Marie accepted the advice and followed it for the rest of her life, as she was never again involved in any political activity. After the 1726 crisis and until the birth of a dauphin in 1729, Cardinal Fleury and the Princess of Carignano made long running preparations to replace Marie, preferably with Charlotte of Hesse-Rheinfels-Rotenburg, if she should die in childbirth.
9626_32	Marie reconciled with Cardinal Fleury, whom she kept contact with through letters and humbly entrusted to advise her how to behave in order to please the King. Fleury and Marie developed a cordial relationship and he often granted her his support when he estimated that her request to the King was harmless; such as in 1742, when the Cardinal, on her request, persuaded the King to allow her to appoint her personal friend Amable-Gabrielle de Villars as Dame d'atours. Her political activity after 1726 was limited to asking Louis XV to grant a pension or a promotion to a friend, and she often used Cardinal Fleury as a mediator to achieve this.
9626_33	Despite her lack of influence, she did have political views, and also some indirect political importance. During the War of the Polish Succession in 1733–1736, she supported her father's candidacy to the Polish throne, and upon her father's demand, she did her best to encourage Cardinal Fleury to support her father's candidacy, though she herself expressed to the Cardinal that she had never wished for the war and that she was an innocent cause of it because the French wished to enhance her dynastic status. After the war, her father was given the Duchy of Lorraine because he was the father-in-law of the King of France, and the Duchy became part of France after the death of her father who became Duke of Lorraine, thus making herself indirectly useful in the political arena. As a devout Catholic, Queen Marie gave her passive support to the so-called Dévots party at court, supported the bishops in their conflicts with the Parliament of Paris, and expressed sympathy for the Jesuit order in
9626_34	their conflict with the crown. It was also a fact, that if the King should die before his son was an adult, then she would in accordance with custom have become regent of France until his 13th birthday, which made Marie a potential regent from the birth of the dauphin until his 13th-birthday, a fact which would have been well known at court.
9626_35	Role as queen Queen Marie was initially not respected by the royal court, where she was regarded as low-born. Her lack of dynastic status and lack of connections left her without a political power base, and she did not manage to acquire any personal or political influence. She was not credited with any personal significance and not given much personal attention outside of her ceremonial role as queen.
9626_36	As queen, Marie Leszczyńska performed her ceremonial role in strict accordance with formal court etiquette and regularly and punctually fulfilled all representational duties that the court life at Versailles demanded of her. She valued the ritualized pomp and court presentations in order to increase her dignity and win the respect of the court nobility, which was necessary because she had no prestigious dynastic connections of birth and was thus initially seen as low born by them: her successor as queen, Marie Antoinette, was to ignore many of these rules, and once pointed out, that in contrast to her predecessor Queen Marie Leszczyńska, it was not necessary for her to enhance her status and dignity since her dynastic status was evident by birth, and that she could therefore afford to relax on her etiquette without losing respect.
9626_37	Marie was given an allowance of 100.000 livres for pleasure, charity and gambling, a sum which was in reality often irregularly paid and also insufficient, as she was often in debt. Though she had simple habits, her apartments at Versailles were not redecorated after 1737 - her favorite game, cavagnole, often placed her in debt, and the King was normally unwilling to pay these off for her.

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