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Oligomerization of Cavbeta subunits is an essential correlate of Ca2+ channel activity.

ABSTRACT: 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 ?(1C) subunit associated with cytosolic Ca(v)? subunits. All major Ca(v)?s share a highly homologous membrane associated guanylate kinase-like (MAGUK) domain that binds to ?(1C) at the ?-interaction domain (AID), a short motif in the linker between transmembrane repeats I and II. In this study we show that Ca(v)? 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)?s oligomerize at the ?(1C) subunits residing in the plasma membrane and bind to the AID. However, Ca(v)? oligomerization occurs independently on the association with ?(1C). Molecular structures responsible for Ca(v)? oligomerization reside in 3 regions of the guanylate kinase subdomain of MAGUK. An augmentation of Ca(v)? 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)? subunits represents a novel and essential aspect of calcium channel regulation.

SUBMITTER: Lao QZ

PROVIDER: S-EPMC2992367 | biostudies-literature | 2010 Dec

REPOSITORIES: biostudies-literature

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Oligomerization of Cavbeta subunits is an essential correlate of Ca2+ channel activity.

Lao Qi Zong QZ Kobrinsky Evgeny E Liu Zhuo Z Soldatov Nikolai M NM

FASEB journal : official publication of the Federation of American Societies for Experimental Biology 20100823 12

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 tha ...[more]

PMID: 20732952

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Project description:Arachidonic acid (AA) inhibits the activity of several different voltage-gated Ca(2+) channels by an unknown mechanism at an unknown site. The Ca(2+) channel pore-forming subunit (Ca(V)alpha(1)) is a candidate for the site of AA inhibition because T-type Ca(2+) channels, which do not require accessory subunits for expression, are inhibited by AA. Here, we report the unanticipated role of accessory Ca(V)beta subunits on the inhibition of Ca(V)1.3b L-type (L-) current by AA. Whole cell Ba(2+) currents were measured from recombinant channels expressed in human embryonic kidney 293 cells at a test potential of -10 mV from a holding potential of -90 mV. A one-minute exposure to 10 microM AA inhibited currents with beta(1b), beta(3), or beta(4) 58, 51, or 44%, respectively, but with beta(2a) only 31%. At a more depolarized holding potential of -60 mV, currents were inhibited to a lesser degree. These data are best explained by a simple model where AA stabilizes Ca(V)1.3b in a deep closed-channel conformation, resulting in current inhibition. Consistent with this hypothesis, inhibition by AA occurred in the absence of test pulses, indicating that channels do not need to open to become inhibited. AA had no effect on the voltage dependence of holding potential-dependent inactivation or on recovery from inactivation regardless of Ca(V)beta subunit. Unexpectedly, kinetic analysis revealed evidence for two populations of L-channels that exhibit willing and reluctant gating previously described for Ca(V)2 channels. AA preferentially inhibited reluctant gating channels, revealing the accelerated kinetics of willing channels. Additionally, we discovered that the palmitoyl groups of beta(2a) interfere with inhibition by AA. Our novel findings that the Ca(V)beta subunit alters kinetic changes and magnitude of inhibition by AA suggest that Ca(V)beta expression may regulate how AA modulates Ca(2+)-dependent processes that rely on L-channels, such as gene expression, enzyme activation, secretion, and membrane excitability.

Dataset Information

Oligomerization of Cavbeta subunits is an essential correlate of Ca2+ channel activity.

Publications

Oligomerization of Cavbeta subunits is an essential correlate of Ca2+ channel activity.

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