The Role of Auxiliary Subunits for the Functional Diversity of Voltage‐Gated Calcium Channels

Campiglio, Marta; Flucher, Bernhard E.

doi:10.1002/jcp.24998

Cited by 87 publications

(63 citation statements)

References 133 publications

(227 reference statements)

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“…Ca V α1 subunits contain five large cytoplasmic domains representing putative binding sites for cytoplasmic modulator and effector proteins: namely, the N terminus; the I-II, II-II, III-IV loops; and the C terminus (8,9). We hypothesized that if any of these cytoplasmic regions of Ca V 1.2 contains sequences essential for the binding of STAC proteins, replacing it with the corresponding sequences of distantly related calcium channels would lead to loss of STAC association.…”

Section: Resultsmentioning

confidence: 99%

STAC Proteins Associate to the IQ Domain of CaV1.2 and Inhibit Calcium-Dependent Inactivation

Campiglio

Bagneaux

Ortner

et al. 2018

Biophysical Journal

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The adaptor proteins STAC1, STAC2, and STAC3 represent a newly identified family of regulators of voltage-gated calcium channel (Ca V ) trafficking and function. The skeletal muscle isoform STAC3 is essential for excitation-contraction coupling and its mutation causes severe muscle disease. Recently, two distinct molecular domains in STAC3 were identified, necessary for its functional interaction with Ca V 1.1: the C1 domain, which recruits STAC proteins to the calcium channel complex in skeletal muscle triads, and the SH3-1 domain, involved in excitation-contraction coupling. These interaction sites are conserved in the three STAC proteins. However, the molecular domain in Ca V 1 channels interacting with the STAC C1 domain and the possible role of this interaction in neuronal Ca V 1 channels remained unknown. Using Ca V 1.2/2.1 chimeras expressed in dysgenic (Ca V 1.1) myotubes, we identified the amino acids 1,641-1,668 in the C terminus of Ca V 1.2 as necessary for association of STAC proteins. This sequence contains the IQ domain and alanine mutagenesis revealed that the amino acids important for STAC association overlap with those making contacts with the C-lobe of calcium-calmodulin (Ca/CaM) and mediating calcium-dependent inactivation of Ca V 1.2. Indeed, patch-clamp analysis demonstrated that coexpression of either one of the three STAC proteins with Ca V 1.2 opposed calcium-dependent inactivation, although to different degrees, and that substitution of the Ca V 1.2 IQ domain with that of Ca V 2.1, which does not interact with STAC, abolished this effect. These results suggest that STAC proteins associate with the Ca V 1.2 C terminus at the IQ domain and thus inhibit calcium-dependent feedback regulation of Ca V 1.2 currents.ecently STAC3 (SH3 and cysteine-rich containing protein 3) has been identified as an essential regulator of calcium channel trafficking and function in skeletal muscle excitationcontraction (EC) coupling and a mutation in STAC3 has been linked to the severe muscle disease Native American myopathy (NAM) (1, 2). Expression of STAC3 is restricted to skeletal muscle, where STAC3 associates with the voltage-gated calcium channel Ca V 1.1 and is involved in mediating voltage-induced calcium release from the sarcoplasmic reticulum (3, 4). In nonmuscle cells, STAC3 was shown to facilitate functional membrane expression of Ca V 1.1 and alter the current properties of Ca V 1.2 (5), suggesting a role of STAC proteins as an L-type calcium channel (Ca V 1) regulator. STAC3 belongs to a family of adaptor proteins that comprises two additional isoforms, STAC1 and STAC2, which are highly expressed in the brain (1).All three STAC proteins contain one C1 domain and two SH3 protein interaction domains (6). We previously demonstrated that the stable association of STAC3 to the Ca V 1 channel complex in the triads of skeletal muscle relies on the C1 domain (7). In contrast, the NAM mutation, which impairs EC coupling and is located in the SH3-1 domain of STAC3 (2-4), did not abolish the interaction with ...

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Section: Resultsmentioning

confidence: 99%

STAC Proteins Associate to the IQ Domain of CaV1.2 and Inhibit Calcium-Dependent Inactivation

Campiglio

Bagneaux

Ortner

et al. 2018

Biophysical Journal

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“…These accessory subunits also modulate the voltage dependence and the gating kinetics of VGCCs (209). There are four genes that encode the β-subunits (β 1–4 ) and four that encode the α 2 δ subunits (α 2 δ 1–4 ) (195, 209). Both are also subject to alternative splicing (195, 209).…”

Section: Voltage-gated Ca2+ Channelsmentioning

confidence: 99%

“…There are four genes that encode the β-subunits (β 1–4 ) and four that encode the α 2 δ subunits (α 2 δ 1–4 ) (195, 209). Both are also subject to alternative splicing (195, 209). Vascular SMCs express β 2 (283), β 3 (745, 1038, 1039), α 2 δ 1 (87, 88, 283) and α 2 δ 3 (283) isoforms of these accessory subunits.…”

Section: Voltage-gated Ca2+ Channelsmentioning

confidence: 99%

Smooth Muscle Ion Channels and Regulation of Vascular Tone in Resistance Arteries and Arterioles

Tykocki

Boerman

Jackson

2017

Comprehensive Physiology

282

347

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Vascular tone of resistance arteries and arterioles determines peripheral vascular resistance, contributing to the regulation of blood pressure and blood flow to, and within the body’s tissues and organs. Ion channels in the plasma membrane and endoplasmic reticulum of vascular smooth muscle cells (SMCs) in these blood vessels importantly contribute to the regulation of intracellular Ca2+ concentration, the primary determinant of SMC contractile activity and vascular tone. Ion channels provide the main source of activator Ca2+ that determines vascular tone, and strongly contribute to setting and regulating membrane potential, which, in turn, regulates the open-state-probability of voltage gated Ca2+ channels (VGCCs), the primary source of Ca2+ in resistance artery and arteriolar SMCs. Ion channel function is also modulated by vasoconstrictors and vasodilators, contributing to all aspects of the regulation of vascular tone. This review will focus on the physiology of VGCCs, voltage-gated K+ (KV) channels, large-conductance Ca2+-activated K+ (BKCa) channels, strong-inward-rectifier K+ (KIR) channels, ATP-sensitive K+ (KATP) channels, ryanodine receptors (RyRs), inositol 1,4,5-trisphosphate receptors (IP3Rs), and a variety of transient receptor potential (TRP) channels that contribute to pressure-induced myogenic tone in resistance arteries and arterioles, the modulation of the function of these ion channels by vasoconstrictors and vasodilators, their role in the functional regulation of tissue blood flow and their dysfunction in diseases such as hypertension, obesity, and diabetes.

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“…43 While the role of g subunits in a functional VGCC is not entirely clear, it is thought that they act mainly as auxiliary subunits of AMPA receptors. 127 The composition and dynamic nature of the channel complex is a major source for functional variability of VGCC (for recent review see 24). Here, the diversity in the expression profile of auxiliary b and a2d-subunit isoforms in neurons produces a large number of possible combinations with a1-subunits and hence major potential for altering calcium channel activity.…”

Section: Voltage-gated Calcium Channelsmentioning

confidence: 99%

Surface dynamics of voltage-gated ion channels

et al. 2016

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Neurons encode information in fast changes of the membrane potential, and thus electrical membrane properties are critically important for the integration and processing of synaptic inputs by a neuron. These electrical properties are largely determined by ion channels embedded in the membrane. The distribution of most ion channels in the membrane is not spatially uniform: they undergo activity-driven changes in the range of minutes to days. Even in the range of milliseconds, the composition and topology of ion channels are not static but engage in highly dynamic processes including stochastic or activity-dependent transient association of the pore-forming and auxiliary subunits, lateral diffusion, as well as clustering of different channels. In this review we briefly discuss the potential impact of mobile sodium, calcium and potassium ion channels and the functional significance of this for individual neurons and neuronal networks.

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The Role of Auxiliary Subunits for the Functional Diversity of Voltage‐Gated Calcium Channels

Cited by 87 publications

References 133 publications

STAC Proteins Associate to the IQ Domain of CaV1.2 and Inhibit Calcium-Dependent Inactivation

STAC Proteins Associate to the IQ Domain of CaV1.2 and Inhibit Calcium-Dependent Inactivation

Smooth Muscle Ion Channels and Regulation of Vascular Tone in Resistance Arteries and Arterioles

Surface dynamics of voltage-gated ion channels

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