Structure and function of the β subunit of voltage-gated Ca²⁺ channels

Abstract

The voltage-gated Ca²⁺ channel β subunit (Ca(v)β) is a cytosolic auxiliary subunit that plays an essential role in regulating the surface expression and gating properties of high-voltage activated (HVA) Ca²⁺ channels. It is also crucial for the modulation of HVA Ca²⁺ channels by G proteins, kinases, Ras-related RGK GTPases, and other proteins. There are indications that Ca(v)β may carry out Ca²⁺ channel-independent functions. Ca(v)β knockouts are either non-viable or result in a severe pathophysiology, and mutations in Ca(v)β have been implicated in disease. In this article, we review the structure and various biological functions of Ca(v)β, as well as recent advances. This article is part of a Special Issue entitled: Calcium channels.

Figure 1

VGCC topology and the structure of the Ca_vβ core in complex with the AID. (A) Schematic representation of the predicted transmembrane topology of the α₁ subunit of VGCC. The AID, marked in red, is located on the I-II linker. ‘P’ indicates the pore loops, located between transmembrane regions S5 and S6. ‘+’ indicates the charged amino acids in S4 – the voltage sensor. (B) Amino acid sequence alignment of the AID from the indicated calcium channel α₁ subunits. Residues involved in interactions with Ca_vβ are marked in red, with the most critical residues underlined. Residue numbers are indicated on both sides of the sequence. (C) Ca_vβ is organized into 5 regions represented schematically in the upper panel. The lower panel shows the crystal structure of the Ca_vβ₃ core in complex with the AID (PDB accession code 1VYT) with the following regions: N-terminus (light blue), the SH3 domain (gold), part of the HOOK region (purple, residues 121-169), and the GK domain (green). Residues 137-166 of the HOOK region were disordered and are not included. The AID region of Ca_v1.2 (residues 422 to 446) is colored in orange.

Figure 2

Major functions of Ca_vβ. (A) Ca_vβ enhances Ca_vα₁ localization to the plasma membrane by preventing Ca_vα₁ degradation and exposing ER export signals on Ca_vα₁. (B) Ca_vβ promotes VGCC gating, resulting in an overall enhancement of current. (C) Ca_vβ interacts with the ryanodine receptor (RYR) in the sarcoplasmic reticulum (SR) of muscle cells and is critical for excitation-contraction coupling. (D) Ca_vβ can be translocated into the nucleus where it may participate in transcriptional regulation. (E) Ca_vβ interacts directly with many intracellular proteins that regulate VGCC function. The strongest of those regulators are RGK proteins, which potently inhibit VGCCs (reviewed in this issue by Colecraft and colleagues, also see [7]). Other partners include ion channels (e.g., BK_Ca and bestrophin), synaptic proteins (e.g., synaptotagmin I and RIMI), and signaling proteins (such as kinases, phosphatases, dynamin, and Ahnak) [for extensive review see 7].

Figure 3

Modulation of HVA Ca²⁺ channel gating by Ca_vβ. (A) Activation: Ca_vβ shifts the current-voltage curve (left panel) and the activation curve (right panel) to more hyperpolarized voltages. (B) Inactivation: Ca_vβ shifts the voltage dependence of inactivation to more hyperpolarized voltages, except β_2a, which shifts it to more depolarized voltages (left panel). All Ca_vβ subunits speed the kinetics of inactivation, except β_2a, which slows the kinetics of channel inactivation (right panel). All traces are schematic representations.