Abstract
Allosteric interactions in ion channels serve to sharpen the control of environmental influences on conductance. We investigated the thermodynamic and kinetic properties of a multi-allosteric K+ channel model possessing three distinct regulatory sites on each of four homologous subunits. Each site was characterized by a bistable free energy landscape with equilibrium constant J, K, or P that was sensitive to a particular environmental variable, as well the activation state of neighboring domains (see figure). The P domain comprising the central pore domain was defined by strong nearest-neighbor interactions that, combined with a counter-balancing bias in P, raised the energy and significantly shortening the dwell times of subconductance states. The mean number of activated regulatory sites was derived from the partition function through linkage analysis. A numbering scheme based on subunit occupancies of the 23 single-subunit activation states generated 330 energetically distinct kinetic states. Solutions to the rate equations simulated unique features attributed to different voltage-dependent K+ channels (for example, intermediate pore activation states in the BK channel, and the rising phase and relationship with activation charge displacement observed in Shaker gating currents), supporting the feasibility of using a modular allosteric approach to K+ channel activation.
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