Title: Cellular function given parametric variation: excitability in the Hodgkin-Huxley model,
Abstract: How is reliable physiological function maintained in cells despite
considerable variability in the values of key parameters of multiple
interacting processes that govern that function? Here we use the classic
Hodgkin-Huxley formulation of the squid giant axon action potential to propose
a possible approach to this problem. Although the full Hodgkin-Huxley model is
very sensitive to fluctuations that independently occur in its many parameters,
the outcome is in fact determined by simple combinations of these parameters
along two physiological dimensions: Structural and Kinetic (denoted $S$ and
$K$). Structural parameters describe the properties of the cell, including its
capacitance and the densities of its ion channels. Kinetic parameters are those
that describe the opening and closing of the voltage-dependent conductances.
The impacts of parametric fluctuations on the dynamics of the system, seemingly
complex in the high dimensional representation of the Hodgkin-Huxley model, are
tractable when examined within the $S-K$ plane. We demonstrate that slow
inactivation, a ubiquitous activity-dependent feature of ionic channels, is a
powerful local homeostatic control mechanism that stabilizes excitability amid
changes in structural and kinetic parameters.