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Regulation of Maximal Open Probability Is a Separable Function of Ca_vß Subunit in L-type Ca²⁺ Channel, Dependent on NH₂ Terminus of _1C (Ca_v1.2)

Department of Physiology and Pharmacology, Sackler School of Medicine, Tel Aviv University, Ramat Aviv 69978, Israel

Correspondence to Nathan Dascal: dascaln{at}post.tau.ac.il

ß subunits (Ca_vß) increase macroscopic currents of voltage-dependent Ca²⁺ channels (VDCC) by increasing surface expression and modulating their gating, causing a leftward shift in conductance–voltage (G-V) curve and increasing the maximal open probability, P_o,max. In L-type Ca_v1.2 channels, the Ca_vß-induced increase in macroscopic current crucially depends on the initial segment of the cytosolic NH₂ terminus (NT) of the Ca_v1.2 (_1C) subunit. This segment, which we term the "NT inhibitory (NTI) module," potently inhibits long-NT (cardiac) isoform of _1C that features an initial segment of 46 amino acid residues (aa); removal of NTI module greatly increases macroscopic currents. It is not known whether an NTI module exists in the short-NT (smooth muscle/brain type) _1C isoform with a 16-aa initial segment. We addressed this question, and the molecular mechanism of NTI module action, by expressing subunits of Ca_v1.2 in Xenopus oocytes. NT deletions and chimeras identified aa 1–20 of the long-NT as necessary and sufficient to perform NTI module functions. Coexpression of ß_2b subunit reproducibly modulated function and surface expression of _1C, despite the presence of measurable amounts of an endogenous Ca_vß in Xenopus oocytes. Coexpressed ß_2b increased surface expression of _1C approximately twofold (as demonstrated by two independent immunohistochemical methods), shifted the G-V curve by 14 mV, and increased P_o,max 2.8–3.8-fold. Neither the surface expression of the channel without Ca_vß nor ß_2b-induced increase in surface expression or the shift in G-V curve depended on the presence of the NTI module. In contrast, the increase in P_o,max was completely absent in the short-NT isoform and in mutants of long-NT _1C lacking the NTI module. We conclude that regulation of P_o,max is a discrete, separable function of Ca_vß. In Ca_v1.2, this action of Ca_vß depends on NT of _1C and is _1C isoform specific.

Abbreviations used in this paper: aa, amino acid; AID, -interaction domain; CT, COOH terminus; HA, hemagglutinin; HEK, human embryonic kidney; NT, NH₂ terminus; NTI, NT inhibitory; PM, plasma membrane; P_o, open probability; VDCC, voltage-dependent calcium channel; VDI, voltage-dependent inactivation.

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