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calcium channel, voltage-dependent, beta 1 subunit
CACNB1 (also known as CAB1; CCHLB1; CACNLB1; MGC41896) encodes a calcium channel beta subunit. It plays an important role in the calcium channel by modulating G protein inhibition, increasing peak calcium current, controlling the alpha-1 subunit membrane targeting and shifting the voltage dependence of activation and inactivation. Alternative splicing occurs at this locus and three transcript variants encoding three distinct isoforms have been identified.
Cacnb1 : calcium channel, voltage-dependent, beta 1 subunit
CaV1.1 is a large transmembrane protein which contains both the Ca2+ conducting pore and the voltage sensing S4 domain. Four other auxiliary subunits bind CaV1.1 to make up DHPR (dihydropyridine receptor, that serves as a modest L-type Ca2+ channel but is primarily known for its function as a voltage sensor. For review, see Flucher et al. 2005 ), with the most widely studied being the cytosolic CaVβ1a (cacnb1) subunit. CaVβ1a, a muscle specific member of the CaVβ family of proteins, binds to a region of the I–II intracellular loop of CaV1.1 known as the alpha interaction domain (AID) (Chen et al. 2004 ). The correct organization of CaV1.1 into tetrads within the t-tubule membrane is a specific function of the CaVβ1a isoform (Schredelseker et al. 2005 ).
The b1a subunit has important effects on the surface expression of alpha-1 subunits, e.g. Cav1.1. cacnb1 subunit produces major changes in the amplitude of L-type currents without any effect on charge movement. (García )
Although classically known for augmenting the expression and function of CaV1 subfamily of calcium channels, the CaVβ family of subunits may contribute to the down-regulation of CaV1 as well (Taylor et al. ). A family of Ras-related G-proteins (RGKs) mediate the down-regulation of several CaV1 isoforms in a CaVβ dependent manner (Beguin et al. 2001 ). Additionally, the previously uncharacterized SH3 domain of CaVβ was shown to bind dynamin and mediate endocytosis of CaV1.2 (Gonzalez-Gutierrez et al. 2007 ).
CaVβ1a is classically described by its role in chaperoning CaV1.1 to the plasma membrane and regulating L-type Ca2+ current (Gregg et al. 1996 ; Strube et al. 1996 ; Beurg et al. 1997 ; Neuhuber et al. 1998 ). Most notably, excitation-contraction (E-C) coupling cannot occur without CaVβ1a (Gregg et al. 1996 ). CaVβ1a binds to charged residues on RyR (Cheng et al. 2005 ) and neutralization of these residues reduces E-C coupling, suggesting a direct interaction with ryanodine receptor (RyR). The correct organization of CaV1.1 into tetrads within the t-tubule membrane is also a specific function of the CaVβ1a isoform (Schredelseker et al. 2005 ).
Experimental overexpression of CaVβ1a reduces both the expression of CaV1.1 and specific force in dissociated single fibers of young mice. Additionally, siRNA inhibition of CaVβ1a restores charge movement in aged muscle. These findings suggest that overexpression of CaVβ1a with aging contributes to excitation-contraction uncoupling by reducing the level of CaV1.1. (Taylor )