The β Subunit of Voltage-Gated Ca²⁺Channels

Abstract

Calcium regulates a wide spectrum of physiological processes such as heartbeat, muscle contraction, neuronal communication, hormone release, cell division, and gene transcription. Major entry-ways for Ca2+ in excitable cells are high-voltage activated (HVA) Ca2+channels. These are plasma membrane proteins composed of several subunits, including α1, α2δ, β, and γ. Although the principal α1 subunit (Cavα1) contains the channel pore, gating machinery and most drug binding sites, the cytosolic auxiliary β subunit (Cavβ) plays an essential role in regulating the surface expression and gating properties of HVA Ca2+ channels. Cavβ is also crucial for the modulation of HVA Ca2+ channels by G proteins, kinases, and the Ras-related RGK GTPases. New proteins have emerged in recent years that modulate HVA Ca2+ channels by binding to Cavβ. There are also indications that Cavβ may carry out Ca2+ channel-independent functions, including directly regulating gene transcription. All four subtypes of Cavβ, encoded by different genes, have a modular organization, consisting of three variable regions, a conserved guanylate kinase (GK) domain, and a conserved Src-homology 3 (SH3) domain, placing them into the membrane-associated guanylate kinase (MAGUK) protein family. Crystal structures of Cavβs reveal how they interact with Cavα1, open new research avenues, and prompt new inquiries. In this article, we review the structure and various biological functions of Cavβ, with both a historical perspective as well as an emphasis on recent advances.

Mutations in voltage-gated L-type calcium channel: implications in cardiac arrhythmia

“…Mechanistically, Ca V β works as a chaperone for the α subunit, and its β-interaction domain (BID) binds with the reserved α-interaction domain (AID) located at I-II loop of Ca V α 1 subunit, enhancing the trafficking of the channels from endoplasmic/sarcoplasmic reticulum (ER/SR) to cell membrane [24,26]. To date, 4 genes encoding β subunits (β 1-4 ) have been identified [27,28]; of which, Ca V β 2 subunit, encoded by CACNB2 gene, is the dominant variant expressed in the heart [29], which has at least 8 distinct splice variants (β 2a-h ) [30,31]. …”

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

“…[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. [12][13][14][15][16][17][18] Among the 5 regions of b subunit, N-terminus plays a key role in determining the subcellular localization of the b subunit, which is principally engaged in modulating the gating kinetics and membrane phospholipid sensitivity 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. [12][13][14][15][16][17][18] Among the 5 regions of b subunit, N-terminus plays a key role in determining the subcellular localization of the b subunit, which is principally engaged in modulating the gating kinetics and membrane phospholipid sensitivity of Ca V channels. [19][20][21][22][23] The Ca V channel with membrane-anchored b subunit, such as b2a or b2e, exhibits relatively slow current inactivation and low sensitivity to the depletion of phosphatidylinositol 4,5-bisphosphate (PIP 2 ), whereas channels with cytosolic b subunit, such as b2b or b3, exhibit the opposite responses.…”

Differential interaction of β2e with phosphoinositides: A comparative study between β2e and MARCKS

“…4 In particular, b subunits have a strong influence on the biophysical property of Ca V channel gating. 5,6 With 4 isotypes, b subunits are usually located in the cytosol and bind to the Ca V channel via the a-interacting domain. However, b2a and b2e subunits are tethered to the plasma membrane even in the absence of a1.…”