Oligomerization of Ca v β subunits is an essential correlate of Ca ²⁺ channel activity

Voltage‐gated calcium channels conduct Ca 2+ ions in response to membrane depolarization. The resulting transient increase in cytoplasmic free calcium concentration is a critical trigger for the initiation of such vital responses as muscle contraction and transcription. L‐type Ca v 1.2 calcium channels are complexes of the pore‐forming α 1C subunit associated with cytosolic Ca v β subunits. All major Ca v βs share a highly homologous membrane associated guanylate kinase‐like (MAGUK) domain that binds to α 1C at the α‐inter‐action domain (AID), a short motif in the linker between transmembrane repeats I and II. In this study we show that Ca v β subunits form multimolecular homo‐and heterooligomeric complexes in human vascular smooth muscle cells expressing native calcium channels and in Cos7 cells expressing recombinant Ca v 1.2 channel subunits. Ca v βs oligomerize at the α 1C subunits residing in the plasma membrane and bind to the AID. However, Ca v β oligomerization occurs independently on the association with α 1C . Molecular structures responsible for Ca v β oligomerization reside in 3 regions of the guanylate kinase subdomain of MAGUK. An augmentation of Ca v β homooligomerization significantly increases the calcium current density, while heterooligomerization may also change the voltage‐dependence and inactivation kinetics of the channel. Thus, oligomerization of Ca v β subunits represents a novel and essential aspect of calcium channel regulation.—Lao, Q. Z., Kobrinsky, E., Liu, Z., Soldatov, N. M. Oligomerization of Ca v β subunits is an essential correlate of Ca 2+ channel activity. FASEB J. 24, 5013–5023 (2010). www.fasebj.org