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 entryways for Ca 2+in excitable cells are high-voltage activated (HVA) Ca 2+channels. These are plasma membrane proteins composed of several subunits, including α 1, α 2 δ, β, and γ. Although the principal α 1 subunit (Ca v α 1) contains the channel pore, gating machinery and most drug binding sites, the cytosolic auxiliary β subunit (Ca v β) plays an essential role in regulating the surface expression and gating properties of HVA Ca 2+channels. Ca v β is also crucial for the modulation of HVA Ca 2+channels by G proteins, kinases, and the Ras-related RGK GTPases. New proteins have emerged in recent years that modulate HVA Ca 2+channels by binding to Ca v β. There are also indications that Ca v β may carry out Ca 2+channel-independent functions, including directly regulating gene transcription. All four subtypes of Ca v β, 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 Ca v βs reveal how they interact with Ca v α 1, open new research avenues, and prompt new inquiries. In this article, we review the structure and various biological functions of Ca v β, with both a historical perspective as well as an emphasis on recent advances.