Direct Estimation of CaV1.2 Gating Parameters: Quantification of Voltage Sensor - Pore Transductions and their Modulation by FLP 64176.
2015
Calcium agonists such as FPL 64174 increase macroscopic calcium channel currents and
induce substantial changes in current kinetics. Their molecular mechanism of action is currently unknown.
Here we propose a technique enabling the estimation of FPL 64174 effects on rate constants of
the voltage sensing machinery and pore transitions from macroscopic Ca V 1.2 current kinetics making
use of a hybrid stochastic-deterministic optimization procedure.
Current traces of wild type Ca V 1.2, a channel construct with neutralized segment IIS4 (IIS4 N ) and a pore mutant (A780T)
were fitted to a circular four-state (rest, activated, open, deactivated) channel model in control and FPL 64174 (1 µM).
The estimated rate constants provided novel insights in how structural elements of the voltage sensing unit and the channel
pore influence the action of FPL 64174. The new approach may be applicable for the analysis of drug effects on other
ion channels as well as for quantification of VS transitions and rate constants of pore gating from macroscopic current kinetics.
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