Cav2.3

The role of distal S6 hydrophobic residues in the voltage-dependent gating of Cav2.3 channels.

Related Articles

The role of distal S6 hydrophobic residues in the voltage-dependent gating of Cav2.3 channels.

J Biol Chem. 2007 Jul 27;

Authors: Raybaud A, Baspinar EE, Dionne F, Dodier Y, Sauvé R, Parent L

The hydrophobic locus VAVIM is conserved in the S6 transmembrane segment of domain IV (IVS6) in Cav1 and Cav2 families. Herein we show that glycine substitution of the VAVIM motif in Cav2.3 produced whole-cell currents with inactivation kinetics that were either slower (A1719G = V1720G), similar (V1718G), or faster (I1721G = M1722G) than the wild-type channel. The fast kinetics of I1721G were observed with a = +10 mV shift in its voltage-dependence of activation (E(0.5,act)). In contrast, the slow kinetics of A1719G and V1720G were accompanied by a significant shift of = -20 mV in their E(0.5,act)indicating that the relative stability of the channel closed state was decreased in these mutants. Glycine scan performed in IS6 (V349), IIS6 (I701), and IIIS6 (L1420) at positions predicted to face V1720 (IVS6) also produced slow inactivating currents with hyperpolarizing shifts in the activation and inactivation potentials, again pointing out to a decrease in the stability of the channel closed state. Mutations to other hydrophobic residues at these positions nearly restored the channel gating. Altogether these data indicate that residues at positions equivalent to 1720 exert a critical control upon the relative stability of the channel closed and open states and more specifically, that hydrophobic residues at these positions promote the channel closed state. We discuss a 3-D homology model of Cav2.3 based upon Kv1.2 where hydrophobic residues at positions facing V1720 (IVS6) in IS6, IIS6, and IIIS6 play a critical role in stabilizing the closed state in Cav2.3.

PMID: 17660294 [PubMed - as supplied by publisher]