Regulation of high‐voltage‐activated Ca²⁺ channel function, trafficking, and membrane stability by auxiliary subunits

Abstract

Voltage-gated Ca2+ (CaV) channels mediate Ca2+ ions influx into cells in response to depolarization of the plasma membrane. They are responsible for initiation of excitation-contraction and excitation-secretion coupling, and the Ca2+ that enters cells through this pathway is also important in the regulation of protein phosphorylation, gene transcription, and many other intracellular events. Initial electrophysiological studies divided CaV channels into low-voltage-activated (LVA) and high-voltage-activated (HVA) channels. The HVA CaV channels were further subdivided into L, N, P/Q, and R-types which are oligomeric protein complexes composed of an ion-conducting CaVα1 subunit and auxiliary CaVα2δ, CaVβ, and CaVγ subunits. The functional consequences of the auxiliary subunits include altered functional and pharmacological properties of the channels as well as increased current densities. The latter observation suggests an important role of the auxiliary subunits in membrane trafficking of the CaVα1 subunit. This includes the mechanisms by which CaV channels are targeted to the plasma membrane and to appropriate regions within a given cell. Likewise, the auxiliary subunits seem to participate in the mechanisms that remove CaV channels from the plasma membrane for recycling and/or degradation. Diverse studies have provided important clues to the molecular mechanisms involved in the regulation of CaV channels by the auxiliary subunits, and the roles that these proteins could possibly play in channel targeting and membrane Stabilization.

Constitutive activity of the Ghrelin receptor reduces surface expression of voltage-gated Ca2+ channels in a CaVβ-dependent manner

“…Ca V channels associate with various proteins and these auxiliary subunits influence their trafficking to the plasma membrane (Dolphin, 2016;Felix et al, 2013;Simms and Zamponi, 2012). Ca V β and Ca V α 2 δ are important auxiliary subunits that promote displacement of Ca V α 1 subunits from the endoplasmic reticulum (ER), and influence forward trafficking as well as stability at the plasma membrane (Felix et al, 2013;Dolphin, 2012).…”

Emerging Role of Ca_V1.2 Channels in Proliferation and Migration in Distinct Cancer Cell Lines

“…There are 5 types of VGCC currents named L-, T-, N-, P/Q-, and R-type, which are classified according to their sensitivity to pharmacological blockade, singlechannel conductance kinetics, and voltage dependence [3,26] . According to their voltage activation properties, VGCC can be further classified into 2 broad families called the low-(T-type) and high-(L-, N-, P/Q-, and R-type) threshold-activated channels [3,26] .…”

“…According to their voltage activation properties, VGCC can be further classified into 2 broad families called the low-(T-type) and high-(L-, N-, P/Q-, and R-type) threshold-activated channels [3,26] . More recently, a unified nomenclature has been adopted in which the Ca V 1 subfamily (Ca V 1.1-Ca V 1.4) includes channels that mediate the dihydropyridine (DHP)-sensitive L-type Ca 2+ currents.…”

“…The Ca V 2 subfamily (Ca V 2.1-Ca V 2.3) includes channels that originate from the P/Q-, N-, and R-type Ca 2+ currents, respectively. Lastly, the Ca V 3 subfamily (Ca V 3.1-Ca V 3.3) includes channels that mediate the low-threshold T-type Ca 2+ currents [3,4,26] .…”

The HOOK region of β subunits controls gating of voltage-gated Ca2+ channels by electrostatically interacting with plasma membrane

“…Surface expression of the a1 subunit requires the auxiliary subunits, where they also play critical roles in modulating the biophysical properties of Ca V a1 channel gating. [8][9][10] Among the auxiliary subunits, the b subunit is particularly important in regulating the gating and membrane expression of Ca V channels. [11][12][13] The b subunit can be divided broadly into 5 regions, such as the N and C terminus, the Src homology 3 (SH3), guanylate kinase (GK) domains, and the flexible HOOK region connecting the 2 domains.…”