RT Journal Article
SR Electronic
T1 Dynamic clamp constructed phase diagram of the Hodgkin-Huxley action potential model
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 766154
DO 10.1101/766154
A1 Hillel Ori
A1 Hananel Hazan
A1 Eve Marder
A1 Shimon Marom
YR 2019
UL http://biorxiv.org/content/early/2019/09/12/766154.1.abstract
AB Excitability – a threshold governed transient in transmembrane voltage – is a fundamental physiological process that controls the function of the heart, endocrine, muscles and neuronal tissues. The 1950’s Hodgkin and Huxley explicit formulation provides a mathematical framework for understanding excitability, as the consequence of the properties of voltage-gated sodium and potassium channels. The Hodgkin-Huxley model is more sensitive to parametric variations of protein densities and kinetics than biological systems whose excitability is apparently more robust. It is generally assumed that the model’s sensitivity reflects missing functional relations between its parameters or other components present in biological systems. Here we experimentally construct excitable membranes using the dynamic clamp and voltage-gated potassium ionic channels (Kv1.3) expressed in Xenopus oocytes. We take advantage of a theoretically derived phase diagram, where the phenomenon of excitability is reduced to two dimensions defined as combinations of the Hodgkin-Huxley model parameters. This biological-computational hybrid enabled us to explore functional relations in the parameter space, experimentally validate the phase diagram of the Hodgkin-Huxley model, and demonstrate activity-dependence and hysteretic dynamics due to the impacts of slow inactivation kinetics. The experimental results presented here provide new insights into the gap between technology-guided high-dimensional descriptions, and a lower, physiological dimensionality, within which biological function is embedded.Significance Statement A long-standing issue in physiology concerns the robustness of cellular functions to variations in concentrations and kinetics of biomolecules. The robustness is believed to reflect functional relations between many underlying biological components. Here we study the relationship between sodium and potassium channel parameters and membrane excitability. To this end we used the dynamic clamp, a computer-controlled system that essentially makes it possible to do simulations with biological cells and ionic channels. We established a real-time closed-loop interaction between a genetically controlled population of excitability-relevant ion channels and a low-dimensional mathematical description of excitability. The results provide new insights into how robustness of excitability arises from the properties of ion channels and their interactions.