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BBA - Biomembranes (v.1828, #7)

Editorial Board (pp. i).

Advances in voltage-gated calcium channel structure, function and physiology by Gerald W. Zamponi; Terrance P. Snutch (pp. 1521-1521).

Alternative splicing: Functional diversity among voltage-gated calcium channels and behavioral consequences by Diane Lipscombe; Arturo Andrade; Summer E. Allen (pp. 1522-1529).

Neuronal voltage-gated calcium channels generate rapid, transient intracellular calcium signals in response to membrane depolarization. Neuronal Ca_V channels regulate a range of cellular functions and are implicated in a variety of neurological and psychiatric diseases including epilepsy, Parkinson's disease, chronic pain, schizophrenia, and bipolar disorder. Each mammalian Cacna1 gene has the potential to generate tens to thousands of Ca_V channels by alternative pre-mRNA splicing, a process that adds fine granulation to the pool of Ca_V channel structures and functions. The precise composition of Ca_V channel splice isoform mRNAs expressed in each cell are controlled by cell-specific splicing factors. The activity of splicing factors are in turn regulated by molecules that encode various cellular features, including cell-type, activity, metabolic states, developmental state, and other factors. The cellular and behavioral consequences of individual sites of Ca_V splice isoforms are being elucidated, as are the cell-specific splicing factors that control splice isoform selection. Altered patterns of alternative splicing of Ca_V pre-mRNAs can alter behavior in subtle but measurable ways, with the potential to influence drug efficacy and disease severity. This article is part of a Special Issue entitled: Calcium channels.► Neuronal Ca_V channels are implicated in neurological and psychiatric diseases. ► Cacna1 genes can generate many Ca_V channel isoforms through alternative splicing. ► Cell-specific splicing factors control the pool of Ca_V mRNA splice isoforms. ► Individual splicing events impact cell function and behavior. ► Expression of Ca_V splice isoforms can influence drug efficacy and disease severity.

Keywords: Splicing factor; Disease; Chronic pain; Morphine; Synaptic transmission; G protein coupled receptor; Mu-opioid receptor

Structure and function of the β subunit of voltage-gated Ca2⁺ channels by Zafir Buraei; Jian Yang (pp. 1530-1540).

The voltage-gated Ca2⁺ channel β subunit (Ca_vβ) is a cytosolic auxiliary subunit that plays an essential role in regulating the surface expression and gating properties of high-voltage activated (HVA) Ca2⁺ channels. It is also crucial for the modulation of HVA Ca2⁺ channels by G proteins, kinases, Ras-related RGK GTPases, and other proteins. There are indications that Ca_vβ may carry out Ca2⁺ channel-independent functions. Ca_vβ knockouts are either non-viable or result in a severe pathophysiology, and mutations in Ca_vβ have been implicated in disease. In this article, we review the structure and various biological functions of Ca_vβ, as well as recent advances. This article is part of a Special Issue entitled: Calcium channels.Display Omitted► The Ca2⁺ channel β subunit is required for voltage-gated Ca2⁺ channel function. ► We review the structure and many functions of Ca_vβ. ► Ca_vβ also has functions independent of Ca2⁺ channels. ► Ca_vβ knockouts have severe deficiencies and Ca_vβ is implicated in human disease. ► We provide a perspective for future research in this field.

Keywords: Ion channel; Auxiliary subunit; Calcium channel; Neuron; Synapse; Voltage-gated

The α₂δ subunits of voltage-gated calcium channels by Annette C. Dolphin (pp. 1541-1549).

Voltage-gated calcium channels consist of the main pore-forming α₁ subunit, together, except in the case of the T-type channels, with β and α₂δ and sometimes γ subunits, which are collectively termed auxiliary or accessory subunits. This review will concentrate on the properties and role of the α₂δ subunits of these channels. These proteins are largely extracellular, membrane-associated proteins which influence the trafficking, localization, and biophysical properties of the channels. This article is part of a Special Issue entitled: Calcium channels.Display Omitted► This review discusses the α₂δ subunits of voltage-gated calcium channels. ► The α₂δ subunits are involved in calcium channel trafficking. ► The α₂δ subunits also affect biophysical properties of calcium channel currents. ► The α₂δ subunits are associated with several different pathologies.

Keywords: Abbreviations; DHP; dihydropyridine; DRG; dorsal root ganglion; ER; endoplasmic reticulum; HVA; high-voltage activated; LVA; low voltage-activated; MIDAS; metal ion dependent adhesion site; VWA; von Willebrand factor-ACalcium channel; Auxiliary subunit; Electrophysiology; Alpha2delta

Modulation of low-voltage-activated T-type Ca2⁺ channels by Yuan Zhang; Xinghong Jiang; Terrance P. Snutch; Jin Tao (pp. 1550-1559).

Low-voltage-activated T-type Ca2⁺ channels contribute to a wide variety of physiological functions, most predominantly in the nervous, cardiovascular and endocrine systems. Studies have documented the roles of T-type channels in sleep, neuropathic pain, absence epilepsy, cell proliferation and cardiovascular function. Importantly, novel aspects of the modulation of T-type channels have been identified over the last few years, providing new insights into their physiological and pathophysiological roles. Although there is substantial literature regarding modulation of native T-type channels, the underlying molecular mechanisms have only recently begun to be addressed. This review focuses on recent evidence that the Cav3 subunits of T-type channels, Cav3.1, Cav3.2 and Cav3.3, are differentially modulated by a multitude of endogenous ligands including anandamide, monocyte chemoattractant protein-1, endostatin, and redox and oxidizing agents. The review also provides an overview of recent knowledge gained concerning downstream pathways involving G-protein-coupled receptors. This article is part of a Special Issue entitled: Calcium channels.► Protein kinase-mediated T-channel modulation ► Protein kinase-independent modulation of T-channels ► Regulation of T-channels by modulation of their expression ► New insights into the modulation of T-channels

Keywords: Abbreviations; LVA; low-voltage-activated; HVA; high-voltage-activated; T-type channels; T-type Ca; 2; ⁺; channels; cAMP; cyclic adenosine monophosphate; PKA; protein kinase A; PKC; protein kinase C; PKG; protein kinase G; PTK; protein tyrosine kinase; HEK293; human embryonic kidney 293; CHO cells; Chinese hamster ovary cells; OAG; 1-oleoyl-2-acetyl-sn-glycerol; DAG; diacylglycerol; PLC; phospholipase C; CaMKII; calmodulin-dependent protein kinase II; KCa3.1; Ca; 2; ⁺; -activated K; ⁺; channels of intermediate conductance; Kv; voltage-activated potassium channels; NK1; neurokinin 1; MCP-1; monocyte chemoattractant protein-1; GHRH; growth-hormone-releasing hormone; KLHL1; Kelch-like 1; AEA; N-acyl ethanolamides; PUFA; polyunsaturated fatty acids; GPCR; G-protein-coupled receptor; G; _βγ; G-protein βγ subunits; CCR2; chemokine receptor 2; NMUR1; neuromedin U type 1 receptor; CRFR1; corticotrophin releasing factor receptor 1T-type Ca; 2; ⁺; channel; Cav3; Protein kinase; Calmodulin kinase II; Rho kinase

T-type Ca2⁺ channels in absence epilepsy by Eunji Cheong; Hee-Sup Shin (pp. 1560-1571).

Low-voltage-activated T-type Ca2⁺ channels are highly expressed in the thalamocortical circuit, suggesting that they play a role in this brain circuit. Indeed, low-threshold burst firing mediated by T-type Ca2⁺ channels has long been implicated in the synchronization of the thalamocortical circuit. Over the past few decades, the conventional view has been that rhythmic burst firing mediated by T-type channels in both thalamic reticular nuclie (TRN) and thalamocortical (TC) neurons are equally critical in the generation of thalamocortical oscillations during sleep rhythms and spike-wave-discharges (SWDs).This review broadly investigates recent studies indicating that even though both TRN and TC nuclei are required for thalamocortical oscillations, the contributions of T-type channels to TRN and TC neurons are not equal in the genesis of sleep spindles and SWDs. T-type channels in TC neurons are an essential component of SWD generation, whereas the requirement for TRN T-type channels in SWD generation remains controversial at least in the GBL model of absence seizures. Therefore, a deeper understanding of the functional consequences of modulating each T-type channel subtype could guide the development of therapeutic tools for absence seizures while minimizing side effects on physiological thalamocortical oscillations. This article is part of a Special Issue entitled: Calcium channels.Differential contribution of low-threshold burst firing to absence epilepsy between TRN and TC nucleiDisplay Omitted► The role of T-type Ca2⁺ channels in the genesis of absence epilepsy. ► The role of T-type Ca2⁺ channels in the thalamocortical circuit. ► T-type Ca2⁺ channels have long been implicated in thalamocortical oscillations. ► T-type channels in TC neurons are essential component in SWD generation. ► The requirement for TRN T-type channels in SWD generation remains controversial.

Keywords: T-type Ca; 2; ⁺; channel; Absence epilepsy; Thalamocortical circuit; Burst firing; Oscillations

T-type calcium channels in burst-firing, network synchrony, and epilepsy by Stuart M. Cain; Terrance P. Snutch (pp. 1572-1578).

Low voltage-activated (LVA) T-type calcium channels are well regarded as a key mechanism underlying the generation of neuronal burst-firing. Their low threshold for activation combined with a rapid and transient calcium conductance generates low-threshold calcium potentials (LTCPs), upon the crest of which high frequency action potentials fire for a brief period. Experiments using simultaneous electroencephalography (EEG) and intracellular recordings demonstrate that neuronal burst-firing is a likely causative component in the generation of normal sleep patterns as well as some pathophysiological conditions, such as epileptic seizures. However, less is known as to how these neuronal bursts impact brain behavior, in particular network synchronization. In this review we summarize recent findings concerning the role of T-type calcium channels in burst-firing and discuss how they likely contribute to the generation of network synchrony. We further outline the function of burst-firing and network synchrony in terms of epileptic seizures. This article is part of a Special Issue entitled: Calcium channels.► T-type calcium channels underlie the generation of neuronal burst-firing. ► Burst-firing is likely causative in the generation of epileptic seizures. ► Burst-firing contributes to the generation of network synchrony. ► We outline the function of network synchrony in terms of epileptic seizures.

Keywords: T-type calcium channel; Low-threshold spike; Low-threshold calcium potential; Burst-firing; Neural network; Epilepsy; Thalamocortical system

Control of low-threshold exocytosis by T-type calcium channels by Norbert Weiss; Gerald W. Zamponi (pp. 1579-1586).

Low-voltage-activated (LVA) T-type Ca2⁺ channels differ from their high-voltage-activated (HVA) homologues by unique biophysical properties. Hence, whereas HVA channels convert action potentials into intracellular Ca2⁺ elevations, T-type channels control Ca2⁺ entry during small depolarizations around the resting membrane potential. They play an important role in electrical activities by generating low-threshold burst discharges that occur during various physiological and pathological forms of neuronal rhythmogenesis. In addition, they mediate a previously unrecognized function in the control of synaptic transmission where they directly trigger the release of neurotransmitters at rest. In this review, we summarize our present knowledge of the role of T-type Ca2⁺ channels in vesicular exocytosis, and emphasize the critical importance of localizing the exocytosis machinery close to the Ca2⁺ source for reliable synaptic transmission. This article is part of a Special Issue entitled: Calcium channels.► T-type calcium channels mediate calcium entry near the resting membrane potential. ► Increasing evidence supports a role of T-type channels in low-threshold exocytosis. ► We review their implication in vesicular neurotransmitter release. ► We propose a mechanism by which T-type channels trigger vesicular exocytosis.

Keywords: Calcium channel

Ca_V1.1: The atypical prototypical voltage-gated Ca2⁺ channel by Roger A. Bannister; Kurt G. Beam (pp. 1587-1597).

Ca_V1.1 is the prototype for the other nine known Ca_V channel isoforms, yet it has functional properties that make it truly atypical of this group. Specifically, Ca_V1.1 is expressed solely in skeletal muscle where it serves multiple purposes; it is the voltage sensor for excitation–contraction coupling and it is an L-type Ca2⁺ channel which contributes to a form of activity-dependent Ca2⁺ entry that has been termed Excitation-coupled Ca²⁺ entry. The ability of Ca_V1.1 to serve as voltage-sensor for excitation–contraction coupling appears to be unique among Ca_V channels, whereas the physiological role of its more conventional function as a Ca2⁺ channel has been a matter of uncertainty for nearly 50years. In this chapter, we discuss how Ca_V1.1 supports excitation–contraction coupling, the possible relevance of Ca2⁺ entry through Ca_V1.1 and how alterations of Ca_V1.1 function can have pathophysiological consequences. This article is part of a Special Issue entitled: Calcium channels.Display Omitted► This article reviews the dual functions of the skeletal muscle L-type Ca2⁺ channel. ► Ca_V1.1 is the voltage sensor for excitation–contraction coupling in skeletal muscle. ► Ca_V1.1 also conducts L-type Ca2⁺ current. ► Mutations in Ca_V1.1 have been linked to episodic muscle disorders. ► A Ca_V1.1 variant is involved in development and contributes to myotonic dystrophy 1.

Keywords: Dihydropyridine receptor (DHPR); Ca; _V; 1.1; α; _1S; L-type; Excitation–contraction (EC) coupling; Excitation-coupled Ca; 2; ⁺; entry (ECCE)

What can naturally occurring mutations tell us about Ca_v1.x channel function? by Thomas Stockner; Alexandra Koschak (pp. 1598-1607).

Voltage-gated Ca2⁺ channels allow for Ca2⁺-dependent intracellular signaling by directly mediating Ca2⁺ ion influx, by physical coupling to intracellular Ca2⁺ release channels or functional coupling to other ion channels such as Ca2⁺ activated potassium channels. L-type Ca2⁺ channels that comprise the family of Ca_v1 channels are expressed in many electrically excitable tissues and are characterized by their unique sensitivity to dihydropyridines. In this issue, we summarize genetic defects in L-type Ca2⁺ channels and analyze their role in human diseases (Ca2⁺ channelopathies); e.g. mutations in Ca_v1.2 α1 cause Timothy and Brugada syndrome, mutations in Ca_v1.3 α1 are linked to sinoatrial node dysfunction and deafness while mutations in Ca_v1.4 α1 are associated with X-linked retinal disorders such as an incomplete form of congenital stationary night blindness. Herein, we also put the mutations underlying the channel's dysfunction into the structural context of the pore-forming α1 subunit. This analysis highlights the importance of combining functional data with structural analysis to gain a deeper understanding for the disease pathophysiology as well as for physiological channel function. This article is part of a Special Issue entitled: Calcium channels.Display Omitted► Structural homology model for structure–(dys)function analysis in Ca_v1.x mutants ► Functional ‘hotspots’ for naturally occurring loss- and gain-of-function mutants ► Gain-of-function mutants interfere with voltage sensor coupling to gate opening. ► Intramolecular interaction in LTCC C-termini with pharmacotherapeutic potential

Keywords: L-type calcium channel; Channelopathy; Structure–function analysis; Homology modeling

Cav1.3 and Cav1.2 channels of adrenal chromaffin cells: Emerging views on cAMP/cGMP-mediated phosphorylation and role in pacemaking by D.H.F. Vandael; S. Mahapatra; C. Calorio; A. Marcantoni; E. Carbone (pp. 1608-1618).

Voltage-gated Ca2⁺ channels (VGCCs) are voltage sensors that convert membrane depolarizations into Ca2⁺ signals. In the chromaffin cells of the adrenal medulla, the Ca2⁺ signals driven by VGCCs regulate catecholamine secretion, vesicle retrievals, action potential shape and firing frequency. Among the VGCC-types expressed in these cells (N-, L-, P/Q-, R- and T-types), the two L-type isoforms, Cav1.2 and Cav1.3, control key activities due to their particular activation–inactivation gating and high-density of expression in rodents and humans. The two isoforms are also effectively modulated by G protein-coupled receptor pathways delimited in membrane micro-domains and by the cAMP/PKA and NO/cGMP/PKG phosphorylation pathways which induce prominent Ca2⁺ current changes if opposingly regulated. The two L-type isoforms shape the action potential and directly participate to vesicle exocytosis and endocytosis. The low-threshold of activation and slow rate of inactivation of Cav1.3 confer to this channel the unique property of carrying sufficient inward current at subthreshold potentials able to activate BK and SK channels which set the resting potential, the action potential shape, the cell firing mode and the degree of spike frequency adaptation during spontaneous firing or sustained depolarizations. These properties help chromaffin cells to optimally adapt when switching from normal to stress-mimicking conditions. Here, we will review past and recent findings on cAMP- and cGMP-mediated modulations of Cav1.2 and Cav1.3 and the role that these channels play in the control of chromaffin cell firing. This article is part of a Special Issue entitled: Calcium channels.Display Omitted► Cav1.2 and Cav1.3 L-type channels are highly expressed in mammalian adrenal chromaffin cells. ► Both isoforms are equally up-modulated by cAMP/PKA and down-modulated by NO/cGMP/PKG. ► When opposingly stimulated, PKA and PKG cause up to a factor of ten Ca2⁺ current variations. ► Cav1.3 allows sufficient inward Ca2⁺ current to surge at sub-threshold potentials. ► The Cav1.3 current sets the firing frequency by triggering BK and SK currents.

Keywords: Voltage-gated calcium channel; BK and SK channels; cAMP/PKA and cGMP/PKG modulation; Exocytosis; Catecholamine release; Endocytosis

Mechanisms of conotoxin inhibition of N-type (Ca_v2.2) calcium channels by David J. Adams; Géza Berecki (pp. 1619-1628).

N-type (Ca_v2.2) voltage-gated calcium channels (VGCC) transduce electrical activity into other cellular functions, regulate calcium homeostasis and play a major role in processing pain information. Although the distribution and function of these channels vary widely among different classes of neurons, they are predominantly expressed in nerve terminals, where they control neurotransmitter release. To date, genetic and pharmacological studies have identified that high-threshold, N-type VGCCs are important for pain sensation in disease models. This suggests that N-type VGCC inhibitors or modulators could be developed into useful drugs to treat neuropathic pain. This review discusses the role of N-type (Ca_v2.2) VGCCs in nociception and pain transmission through primary sensory dorsal root ganglion (DRG) neurons (nociceptors). It also outlines the potent and selective inhibition of N-type VGCCs by conotoxins, small disulfide-rich peptides isolated from the venom of marine cone snails. Of these conotoxins, ω-conotoxins are selective N-type VGCC antagonists that preferentially block nociception in inflammatory pain models, and allodynia and/or hyperalgesia in neuropathic pain models. Another conotoxin family, α-conotoxins, were initially proposed as competitive antagonists of muscle and neuronal nicotinic acetylcholine receptors (nAChR). Surprisingly, however, α-conotoxins Vc1.1 and RgIA, also potently inhibit N-type VGCC currents in the sensory DRG neurons of rodents and α9 nAChR knockout mice, via intracellular signaling mediated by G protein-coupled GABA_B receptors. Understanding how conotoxins inhibit VGCCs is critical for developing these peptides into analgesics and may result in better pain management. This article is part of a Special Issue entitled: Calcium channels.Display Omitted► N-type (Ca_v2.2) VGCCs are involved in nociception and are a pain target. ► ω- and α-Conotoxins inhibit N-type VGCCs and can be developed as novel analgesics. ► ω-Conotoxins directly bind to and block Ca_v2.2 channels. ► Analgesic α-conotoxins inhibit N-type VGCCs via G protein-coupled GABA_B receptors. ► Docking models suggest α-conotoxin Vc1.1 binding sites between GABA_B ectodomains.

Keywords: Abbreviations; N-type VGCC; neuronal-type voltage-gated calcium channel; CDI; Ca; 2; ⁺; -dependent inactivation; GPCR; G protein-coupled receptor; GABA; γ-aminobutyric acid; GABA; _B; R; GABA; _B; receptor; siRNA; small interfering RNA; VFT; Venus flytrap module; nAChR; nicotinic acetylcholine receptor; mGluR1; metabotropic glutamate receptor-subtype 1; DRG; dorsal root ganglionNociceptor; Neuropathic pain; N-type calcium channel; ω-Conotoxin; α-Conotoxin; GABA; _B; receptor

Regulation of Ca_V2 calcium channels by G protein coupled receptors by Gerald W. Zamponi; Kevin P.M. Currie (pp. 1629-1643).

Voltage gated calcium channels (Ca2⁺ channels) are key mediators of depolarization induced calcium influx into excitable cells, and thereby play pivotal roles in a wide array of physiological responses. This review focuses on the inhibition of Ca_V2 (N- and P/Q-type) Ca2⁺-channels by G protein coupled receptors (GPCRs), which exerts important autocrine/paracrine control over synaptic transmission and neuroendocrine secretion. Voltage-dependent inhibition is the most widespread mechanism, and involves direct binding of the G protein βγ dimer (Gβγ) to the α1 subunit of Ca_V2 channels. GPCRs can also recruit several other distinct mechanisms including phosphorylation, lipid signaling pathways, and channel trafficking that result in voltage-independent inhibition. Current knowledge of Gβγ-mediated inhibition is reviewed, including the molecular interactions involved, determinants of voltage-dependence, and crosstalk with other cell signaling pathways. A summary of recent developments in understanding the voltage-independent mechanisms prominent in sympathetic and sensory neurons is also included. This article is part of a Special Issue entitled: Calcium channels.Display Omitted► Ca_V2 channels play pivotal roles in neurotransmitter and hormone release. ► G protein coupled receptors orchestrate precise control of Ca_V2 channels. ► Voltage-dependent inhibition is mediated by direct binding of Gβγ to the channels. ► Voltage-independent inhibition is mediated by several other distinct pathways. ► Current understanding of these important mechanisms is provided in this review.

Keywords: Calcium channel; G protein coupled receptor; Gβγ; Tyrosine kinase; PiP2; Arachidonic acid

Regulation of voltage-dependent calcium channels by RGK proteins by Tingting Yang; Henry M. Colecraft (pp. 1644-1654).

RGK proteins belong to the Ras superfamily of monomeric G-proteins, and currently include four members —Rad,Rem,Rem2, andGem/Kir. RGK proteins are broadly expressed, and are the most potent known intracellular inhibitors of high-voltage-activated Ca2⁺ (Ca_V1 and Ca_V2) channels. Here, we review and discuss the evidence in the literature regarding the functional mechanisms, structural determinants, physiological role, and potential practical applications of RGK-mediated inhibition of Ca_V1/Ca_V2 channels. This article is part of a Special Issue entitled: Calcium channels.Display Omitted► RGK proteins inhibit voltage-dependent Ca_V1 and Ca_V2 channels. ► RGKs use multiple mechanisms and determinants to inhibit Ca_V1/Ca_V2 channels. ► The mechanisms of channel inhibition are customized for different RGK/Ca_V channel types. ► New functionalities can be engineered into RGKs for practical applications.

Keywords: Voltage-dependent calcium channel; RGK protein; Rem; Rad; Rem2; Gem

Calcium channels and migraine by Daniela Pietrobon (pp. 1655-1665).

Missense mutations in CACNA1A, the gene that encodes the pore-forming α₁ subunit of human voltage-gated Ca_V2.1 (P/Q-type) calcium channels, cause a rare form of migraine with aura (familial hemiplegic migraine type 1: FHM1). Migraine is a common disabling brain disorder whose key manifestations are recurrent attacks of unilateral headache that may be preceded by transient neurological aura symptoms. This review, first, briefly summarizes current understanding of the pathophysiological mechanisms that are believed to underlie migraine headache, migraine aura and the onset of a migraine attack, and briefly describes the localization and function of neuronal Ca_V2.1 channels in the brain regions that have been implicated in migraine pathogenesis. Then, the review describes and discusses i) the functional consequences of FHM1 mutations on the biophysical properties of recombinant human Ca_V2.1 channels and native Ca_V2.1 channels in neurons of knockin mouse models carrying the mild R192Q or severe S218L mutations in the orthologous gene, and ii) the functional consequences of these mutations on neurophysiological processes in the cerebral cortex and trigeminovascular system thought to be involved in the pathophysiology of migraine, and the insights into migraine mechanisms obtained from the functional analysis of these processes in FHM1 knockin mice. This article is part of a Special Issue entitled: Calcium channels.Display Omitted► Mutations in the Ca_V2.1 channel gene cause a rare form of migraine with aura (FHM1). ► FHM1 mutations produce gain-of-function of neuronal Ca_V2.1 channels. ► FHM1 mutations enhance cortical excitatory transmission but do not affect inhibitory transmission. ► FHM1 mutations facilitate cortical spreading depression. ► FHM1 mutations enhance CGRP release at the trigeminal ganglion but not at the dura.

Keywords: Calcium channel; Migraine; Spreading depression; Channelopathy; Trigeminal ganglion; Cerebral cortex

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BBA - Biomembranes (v.1828, #7)