Untitled

Abstract

Calcium channel beta subunits have profound effects on how alpha1 subunits perform. In this article we summarize our present knowledge of the primary structures of beta subunits as deduced from cDNAs and illustrate their different properties. Upon co-expression with alpha1 subunits, the effects of beta subunits vary somewhat between L-type and non-L-type channels mostly because the two types of channels have different responses to voltage which are affected by beta subunits, such as long-lasting prepulse facilitation of alpha1C (absent in alpha1E) and inhibition by G protein betagamma dimer of alpha1E, absent in alpha1C. One beta subunit, a brain beta2a splice variant that is palmitoylated, has several effects not seen with any of the others, and these are due to palmitoylation. We also illustrate the finding that functional expression of alpha1 in oocytes requires a beta subunit even if the final channel shows no evidence for its presence. We propose two structural models for Ca2+ channels to account for "alpha1 alone" channels seen in cells with limited beta subunit expression. In one model, beta dissociates from the mature alpha1 after proper folding and membrane insertion. Regulated channels seen upon co-expression of high levels of beta would then have subunit composition alpha1beta. In the other model, the "chaperoning" beta remains associated with the mature channel and "alpha1 alone" channels would in fact be alpha1beta channels. Upon co-expression of high levels of beta the regulated channels would have composition [alpha1beta]beta.

Down-regulation of Voltage-gated Ca2+ Channels by Neuronal Calcium Sensor-1 Is β Subunit-specific

“…The Ca 2ϩ channel ␤ subunit is an important determinant of the final Ca 2ϩ current amplitude observed at the oocyte surface membrane and regulates many of its electrophysiological properties (4,31,32). Hence, we tested the role of the ␤ subunit on the effects of NCS-1.…”

“…Several types of Ca 2ϩ channels have been characterized (T, L, N, P/Q, and R) that appear to play a specific role in each of these functions. These channels share a common architecture composed of a major ␣ 1 subunit (for which ten genes are known) tightly associated with regulatory subunits ␣ 2 -␦ (four different genes), ␤ (four genes), and possibly ␥ (eight genes) in a functional multimeric complex (1)(2)(3)(4). This molecular diversity, further expanded by the existence of several splice variants for each of these genes, produces a large number of possible Ca 2ϩ channel subunit combinations with different pharmacological and biophysical properties and specific cellular and subcellular localization (5).…”

Uncoupling of Calcium Channel α1 and β Subunits in Developing Neurons

“…Divergence of ␤ subunit sequences has permitted multiple modulatory functions of ␤ subunits, which act in a cell type and calcium channel-specific manner (6,7). However, the virtual structural invariance of the ␤ subunit core across divergent species and its resemblance to a membrane-associated guanylate kinase scaffolding molecule suggests that a primary role of the ␤ subunit may be to stabilize membrane protein complexes associated with high voltage-activated calcium channels.…”

“…Like other types of high voltage-activated channels, Ca v 2 channels exist as macromolecular complexes of a pore-forming ␣ 1 subunit and ancillary ␤, ␣ 2 -␦, and possibly ␥ subunits (5). The mammalian brain expresses four different types of ␤ subunits that interact to differentially modulate ␣ 1 subunit function (6,7). The functional effects of ␤ subunit coexpression include changes in the voltage dependences and rates of activation and inactivation, plus an increase in current densities (8 -17).…”

The HOOK region of β subunits controls gating of voltage-gated Ca2+ channels by electrostatically interacting with plasma membrane

“…[11][12][13] The b subunit can be divided broadly into 5 regions, such as the N and C terminus, the Src homology 3 (SH3), guanylate kinase (GK) domains, and the flexible HOOK region connecting the 2 domains. [12][13][14][15][16][17][18] Among the 5 regions of b subunit, N-terminus plays a key role in determining the subcellular localization of the b subunit, which is principally engaged in modulating the gating kinetics and membrane phospholipid sensitivity of Ca V channels. [19][20][21][22][23] The Ca V channel with membrane-anchored b subunit, such as b2a or b2e, exhibits relatively slow current inactivation and low sensitivity to the depletion of phosphatidylinositol 4,5-bisphosphate (PIP 2 ), whereas channels with cytosolic b subunit, such as b2b or b3, exhibit the opposite responses.…”