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8.A.22 The Ca2+ Channel Auxiliary Subunit β Types 1-4 (CCA-β) Family

The calcium β auxiliary subunits are cytosolic proteins with no transmembrane segments. Their structures and interaction sites with the α-subunits have been determined (Hanlon and Wallace, 2002van Petegem et al., 2004). Expression of β-subunits has been demonstrated in muscle, heart, lung and other tissues. β-subunits can associate with the membrane even in the absence of the principal α-subunit through an acidic motif or lipid modification. It has been suggested that β-subunit-dependent modulation of N-type calcium channels via the mitogen-activated protein kinase might regulate release of neurotransmitters (Fitzgerald, 2002). Like other subunits in the calcium channel complex, these β-subunits are alternatively spliced and modified post-translationally. It has been reported that α2δ subunits (TC# 8.A.18) require the presence of β-subunits in order to be functional (Dolphin et al., 1999). Many protein of TC families 8.A.22 and 8.A.24 and others contain PDZ, SH3 and kinase domains involved in signal transduction, often interacting with receptors and transporters. Therefore, these two families share about 400 aas iin common.

In animals, calcium regulates heartbeat, muscle contraction, neuronal communication, hormone release, cell division, and gene transcription. Major entryways for Ca2+ in excitable cells are high-voltage activated (HVA) Ca2+ channels, Cav (Buraei and Yang, 2010). These are plasma membrane proteins composed of several subunits, including α1, α2δ, β, and γ. Although the principal α1 subunit contains the channel pore, gating machinery and most drug binding sites, the cytosolic auxiliary β subunit 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. Additional proteins modulate HVA Ca2+ channels by binding to Cavβ, and it 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 (Buraei and Yang, 2010).

Voltage-gated calcium channels conduct Ca2+ 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 Cav1.2 calcium channels are complexes of the pore-forming α1C subunit associated with cytosolic Cavβ subunits. All major Cavβs share a highly homologous membrane associated guanylate kinase-like (MAGUK) domain that binds to α1C at the α-interaction domain (AID), a short motif in the linker between transmembrane repeats I and II. In this study we show that Cavβ subunits form multimolecular homo- and heterooligomeric complexes in human vascular smooth muscle cells expressing native calcium channels and in Cos7 cells expressing recombinant Cav1.2 channel subunits. Cavβs oligomerize at the α1C subunits residing in the plasma membrane and bind to the AID. However, Cavβ oligomerization occurs independently on the association with α1C. Molecular structures responsible for Cavβ oligomerization reside in 3 regions of the guanylate kinase subdomain of MAGUK. An augmentation of Cavβ homooligomerization significantly increases the calcium current density, while heterooligomerization may also change the voltage-dependence and inactivation kinetics of the channel. Thus, oligomerization of Cavβ subunits represents a novel and essential aspect of calcium channel regulation.

References associated with 8.A.22 family:

Buraei, Z. and J. Yang. (2010). The ß subunit of voltage-gated Ca2+ channels. Physiol. Rev. 90: 1461-1506. 20959621
Dolphin, A.C., C.N. Wyatt, J. Richards, R.E. Beattie, P. Craig, J.H. Lee, L.L. Cribbs, S.G. Volsen, and E. Perez-Reyes. (1999). The effect of α2δ and other accessory subunits on expression and properties of the calcium channel α1γ. J. Physiol. 519: 35-45. 10432337
Fitzgerald, E.M. (2002). The presence of Ca2+ channel β-subunit is required for mitogen-activated protein kinase (MAPK)-dependent modulation of α1β Ca2+ channels in COS-7 cells. J. Physiol. 543: 425-437. 12205179
Hanlon, M.R., and B.A. Wallace. (2002). Structure and function of voltage-dependent ion channel regulatory β subunits. Biochemistry 41: 2886-2894. 11863426
Lao, Q.Z., E. Kobrinsky, Z. Liu, and N.M. Soldatov. (2010). Oligomerization of Cavbeta subunits is an essential correlate of Ca2+ channel activity. FASEB J. 24: 5013-5023. 20732952
Li, J., D.J. Callaway, and Z. Bu. (2009). Ezrin induces long-range interdomain allostery in the scaffolding protein NHERF1. J. Mol. Biol. 392: 166-180. 19591839
Van Petegem, F., K.A. Clark, F.C. Chatelain, and D.L. Minor, Jr. (2004). Structure of a complex between a voltage-gated calcium channel β-subunit and an α-subunit domain. Nature 429: 671-675. 15141227