Membrane Voltage More Efficient In Closing Than Opening CaV1.2?

Abstract

Point mutations in a gating-related sequence stretch in the pore-lining segment IIS6 of CaV1.2 (779-782:LAIA motive) convert the high-voltage activated calcium channel into a low-voltage activated one. Here we analyze the changes in current activation and deactivation induced by these and glycine mutations in this region. Our model describes channel activation as voltage-dependent sensor movement and a voltage-independent pore opening and deactivation as voltage-dependent return of the sensor and subsequent pore closure.An inverse problem approach enabled the estimation of current activation and deactivation rate constants from 16 mutants and wild type CaV1.2 with narrow confidence intervals. Current activation, deactivation and steady-state activation of wild type and 12 mutants could be fitted with identical voltage dependencies of the voltage sensing machinery (x(V),y(V)). Steeper voltage dependence of y(V) compared to x(V) (see Figure) suggest that a membrane hyperpolarisation more efficiently closes than a depolarization opens the channel. Mutations in IIS6 of CaV1.2 destabilizing the closed state simultaneously appear to stabilize the open state in all 16 mutants.∗ This study was supported by a grant from FWF (Project P19614-B11).View Large Image | View Hi-Res Image | Download PowerPoint Slide