Open-state occupancy prevents gating charge relaxation of N-type (CaV2.2) calcium channels.
N-type and L-type channels have significant gating differences, and we wondered whether some of these differences are linked to the relationship between charge movement and channel opening. The time constants for N-channel closing (tau(Deact)) and Off-gating charge movement (tauQ(Off)) were compared over a range of voltages. tauQ(Off) was significantly larger than tau(Deact) at voltages < -10 mV, and the voltage dependence of the tauQ(Off) was less steep than that for tau(Deact), which suggests that gating charge relaxation does not limit channel closing. Roscovitine, a drug that slows N-channel closing by holding the channel in a high open-probability state, was found to slow both tauQ(Off) and tau(Deact), and thus the time courses of channel closing and gating charge relaxation were similar. Our gating current results were reproduced with the addition of a voltage-independent, closed-closed transition to our previously published two-open-state N-channel model. This work suggests that, like L-type channels, there is a voltage-independent transition along the N-channel activation/deactivation pathway, but this transition occurs between closed states instead of the closed-open states of the L-channel. Also unlike L-type channels, the gating charge appears to be locked into the activated position by the N-channel open state.
Yarotskyy
Viktor
V
Department of Anesthesiology, Penn State College of Medicine, Penn State University, Hershey, Pennsylvania, USA.
Elmslie
Keith S
KS
D001703:Biophysics / Q000379:methods*; D020746:Calcium Channels, L-Type / Q000737:chemistry* / Q000378:metabolism; D020864:Calcium Channels, N-Type / Q000737:chemistry* / Q000378:metabolism; D002460:Cell Line; D002626:Chemistry, Pharmaceutical / Q000379:methods; D003198:Computer Simulation; D006801:Humans; D007477:Ions; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D018408:Patch-Clamp Techniques; D011336:Probability; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011687:Purines / Q000494:pharmacology; D000077546:Roscovitine; D013997:Time Factors
D020746:Calcium Channels, L-Type; D020864:Calcium Channels, N-Type; D007477:Ions; D047428:Protein Kinase Inhibitors; D011687:Purines; D000077546:Roscovitine