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

Buraei, Zafir; Yang, Jian

doi:10.1016/j.bbamem.2012.08.028

Cited by 113 publications

(136 citation statements)

References 165 publications

(282 reference statements)

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“…The optimal ratio for channel modulation remains to be established. By comparison, a single high affinity intracellular binding site for Ca V ␤ onto the I-II linker of the Ca V ␣1 subunit from high voltage-activated Ca V 1 and Ca V 2 channels has been identified (17,46,(82)(83)(84). Whether a single Ca V ␣2␦1 subunit could interact with two Ca V ␣1 or whether the L-type Ca V 1.2 channel complex (85) can accommodate two or more Ca V ␣2␦1 subunits remains a question for debate.…”

Section: Discussionmentioning

confidence: 99%

Identification of Glycosylation Sites Essential for Surface Expression of the CaVα2δ1 Subunit and Modulation of the Cardiac CaV1.2 Channel Activity

Tétreault¹,

Bourdin²,

Briot³

et al. 2016

Journal of Biological Chemistry

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Alteration in the L-type current density is one aspect of the electrical remodeling observed in patients suffering from cardiac arrhythmias. Changes in channel function could result from variations in the protein biogenesis, stability, post-translational modification, and/or trafficking in any of the regulatory subunits forming cardiac L-type Ca 2؉ channel complexes. Ca V ␣2␦1 is potentially the most heavily N-glycosylated subunit in the cardiac L-type Ca V 1.2 channel complex. Here, we show that enzymatic removal of N-glycans produced a 50-kDa shift in the mobility of cardiac and recombinant Ca V ␣2␦1 proteins. This change was also observed upon simultaneous mutation of the 16 Asn sites. Nonetheless, the mutation of only 6/16 sites was sufficient to significantly 1) reduce the steady-state cell surface fluorescence of Ca V ␣2␦1 as characterized by two-color flow cytometry assays and confocal imaging; 2) decrease protein stability estimated from cycloheximide chase assays; and 3) prevent the Ca V ␣2␦1-mediated increase in the peak current density and voltage-dependent gating of Ca V 1.2. Reversing the N348Q and N812Q mutations in the non-operational sextuplet Asn mutant protein partially restored Ca V ␣2␦1 function. Single mutation N663Q and double mutations N348Q/N468Q, N348Q/N812Q, and N468Q/N812Q decreased protein stability/synthesis and nearly abolished steady-state cell surface density of Ca V ␣2␦1 as well as the Ca V ␣2␦1-induced up-regulation of L-type currents. These results demonstrate that Asn-663 and to a lesser extent Asn-348, Asn-468, and Asn-812 contribute to protein stability/synthesis of Ca V ␣2␦1, and furthermore that N-glycosylation of Ca V ␣2␦1 is essential to produce functional L-type Ca 2؉ channels.The regulation of Ca 2ϩ influx in cardiac cells is critical to the generation of the force necessary for the myocardium to meet the physiological needs of the body (1). In resting cells, intracellular free ionized Ca 2ϩ is maintained at a low concentration (high nanomolar range) by the concerted action of mechanisms that prevent Ca 2ϩ entry, promote its extrusion (mostly via the Na ϩ /Ca 2ϩ exchanger), and ensure its storage in the sarcoplasmic reticulum (2). Ca 2ϩ entry is mediated mainly by the cardiac L-type Ca 2ϩ channel, which is central to the initiation of excitation-contraction coupling via Ca 2ϩ -induced Ca 2ϩ release from the sarcoplasmic reticulum. Regulation of the L-type Ca 2ϩ current has profound physiological significance. Indeed, alterations in density or the activation/inactivation gating of L-type Ca 2ϩ channels have been implicated in a variety of cardiovascular diseases (3, 4), including cardiac arrhythmias such as atrial fibrillation (5-8), heart failure (9, 10), and ischemic heart disease (10). The molecular mechanisms underlying changes in the activity of the L-type Ca 2ϩ channel remain under study for most pathologies.The L-type Ca V 1.2 channel belongs to the molecular family of high voltage-activated Ca V channels. High voltage-activated Ca V 1.2 channels are hetero-oligo...

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Section: Discussionmentioning

confidence: 99%

Identification of Glycosylation Sites Essential for Surface Expression of the CaVα2δ1 Subunit and Modulation of the Cardiac CaV1.2 Channel Activity

Tétreault¹,

Bourdin²,

Briot³

et al. 2016

Journal of Biological Chemistry

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“…The latter are low voltage-activated (LVA) and do not have an AID in their I-II loop and do not require any auxiliary subunits for proper expression or function [3,4]. In contrast, Ca v 1 and Ca v 2 channels (L-, N-, P/Q-and R-type channels) The β subunit binds to the III loop but may also interact with other regions of the channel [3,4]. B, Classification of VGCCs.…”

Section: Voltage-gated Calcium Channelsmentioning

confidence: 99%

RGK regulation of voltage-gated calcium channels

Buraei

Lumen

Kaur

et al. 2015

Sci. China Life Sci.

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Voltage-gated calcium channels (VGCCs) play critical roles in cardiac and skeletal muscle contractions, hormone and neurotransmitter release, as well as slower processes such as cell proliferation, differentiation, migration and death. Mutations in VGCCs lead to numerous cardiac, muscle and neurological disease, and their physiological function is tightly regulated by kinases, phosphatases, G-proteins, calmodulin and many other proteins. Fifteen years ago, RGK proteins were discovered as the most potent endogenous regulators of VGCCs. They are a family of monomeric GTPases (Rad, Rem, Rem2, and Gem/Kir), in the superfamily of Ras GTPases, and they have two known functions: regulation of cytoskeletal dynamics including dendritic arborization and inhibition of VGCCs. Here we review the mechanisms and molecular determinants of RGK-mediated VGCC inhibition, the physiological impact of this inhibition, and recent evidence linking the two known RGK functions. calcium, channel modulation, trafficking, cardiac physiology, neurobiology, beta subunit Citation:

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“…4 In particular, b subunits have a strong influence on the biophysical property of Ca V channel gating. 5,6 With 4 isotypes, b subunits are usually located in the cytosol and bind to the Ca V channel via the a-interacting domain. However, b2a and b2e subunits are tethered to the plasma membrane even in the absence of a1.…”

Section: Introductionmentioning

confidence: 99%

Differential interaction of β2e with phosphoinositides: A comparative study between β2e and MARCKS

Kim

Suh

2016

Channels

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Voltage-gated calcium (Ca V ) channels are responsible for Ca 2C influx in excitable cells. As one of the auxiliary subunits, the Ca V b subunit plays a pivotal role in the membrane expression and receptor modulation of Ca V channels. In particular, the subcellular localization of the b subunit is critical for determining the biophysical properties of Ca V channels. Recently, we showed that the b2e isotype is tethered to the plasma membrane. Such a feature of b2e is due to the reversible electrostatic interaction with anionic membrane phospholipids. Here, we further explored the membrane interaction property of b2e by comparing it with that of myristoylated alanine-rich C kinase substrate (MARCKS). First, the charge neutralization of the inner leaf of the plasma membrane induced the translocation of both b2e and MARCKS to the cytosol, while the transient depletion of poly-phosphoinositides (poly-PIs) by translocatable pseudojanin (PJ) systems induced the cytosolic translocation of b2e but not MARCKS. Second, the activation of protein kinase C (PKC) induced the translocation of MARCKS but not b2e. We also found that after the cytosolic translocation of MARCKS by receptor activation, depletion of poly-PIs slowed the recovery of MARCKS to the plasma membrane. Together, our data demonstrate that both b2e and MARCKS bind to the membrane through electrostatic interaction but with different binding affinity, and thus, they are differentially regulated by enzymatic degradation of membrane PIs.

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

Cited by 113 publications

References 165 publications

Identification of Glycosylation Sites Essential for Surface Expression of the CaVα2δ1 Subunit and Modulation of the Cardiac CaV1.2 Channel Activity

Identification of Glycosylation Sites Essential for Surface Expression of the CaVα2δ1 Subunit and Modulation of the Cardiac CaV1.2 Channel Activity

RGK regulation of voltage-gated calcium channels

Differential interaction of β2e with phosphoinositides: A comparative study between β2e and MARCKS

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