The beta Subunit of Voltage-Gated Ca2+ Channels

Buraei Z, Yang J. The beta Subunit of Voltage-Gated Ca2+ Channels. Physiol Rev 90: 1461-1506, 2010; doi: 10.1152/physrev.00057.2009.-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 alpha(1), alpha(2)delta, beta, and gamma. Although the principal alpha(1) subunit (Ca-v alpha(1)) contains the channel pore, gating machinery and most drug binding sites, the cytosolic auxiliary beta subunit (Ca-v beta) plays an essential role in regulating the surface expression and gating properties of HVA Ca2+ channels. Ca-v beta 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 Ca-v beta. There are also indications that Ca-v beta may carry out Ca2+ channel-independent functions, including directly regulating gene transcription. All four subtypes of Ca-v beta, 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 beta s reveal how they interact with Ca-v alpha(1), open new research avenues, and prompt new inquiries. In this article, we review the structure and various biological functions of Ca-v beta, with both a historical perspective as well as an emphasis on recent advances.