and C2 domain) that display affinity for different phospholipid components of the plasma membrane. It is important to note that research has also discovered that, in addition to the plasma membrane, phosphoinositide phospholipase C also exists within other sub-cellular regions such as the cytoplasm and nucleus of the cell. At present, it is unclear exactly what the definitive roles for these enzymes in these cellular compartments are, particularly the nucleus. Function Phospholipase C performs a catalytic mechanism, depleting PIP2 and generating inositol trisphosphate (IP3) and diacylglycerol (DAG). Depletion of PIP2 inactivates numerous effector molecules in the plasma membrane, most notably PIP2 dependent channels and transporters responsible for setting the cell's membrane potential. The hydrolytic products also go on to modulate the activity of downstream proteins important for cellular signaling. IP3 is soluble, and diffuses through the cytoplasm and interacts with IP3 receptors on the endoplasmic reticulum, causing the release of calcium and raising the level of intracellular calcium. Further reading: Function of calcium in humans DAG remains within the inner leaflet of the plasma membrane due to its hydrophobic character, where it recruits protein kinase C (PKC), which becomes activated in conjunction with binding calcium ions. This results in a host of cellular responses through stimulation of calcium-sensitive proteins such as Calmodulin. Further reading: Function of protein kinase C Domain structure In terms of domain organization, all family members possess homologous X and Y catalytic domains in the form of a distorted Triose Phosphate Isomerase (TIM) barrel with a highly disordered, charged, and flexible intervening linker region. Likewise, all isoforms possess four EF hand domains, and a single C2 domain that flank the X and Y catalytic core. An N-terminal PH domain is present in every family except for the sperm-specific ζ isoform. SH2 (phosphotyrosine binding) and SH3 (proline-rich-binding) domains are found only in the γ form (specifically within the linker region), and only the ε form contains both guanine nucleotide exchange factor (GEF) and RA (Ras Associating) domains. The β subfamily is distinguished from the others by the presence of a long C-terminal extension immediately downstream of the C2 domain, which is required for activation by Gαq subunits, and which plays a role in plasma membrane binding and nuclear localization. Isoenzymes and activation The phospholipase C family consists of 13 isoenzymes split between six subfamilies, PLC-δ (1,3 & 4), -β(1-4), -γ(1,2), -ε, -ζ, and the recently discovered -η(1,2) isoform.