Voltage-Gated Calcium Channels
01 Aug 2011-Cold Spring Harbor Perspectives in Biology (Cold Spring Harbor Laboratory Press)-Vol. 3, Iss: 8, pp 897-909
TL;DR: The molecular relationships and physiological functions of these voltage-gated Ca(2+) channel proteins are presented and information on their molecular, genetic, physiological, and pharmacological properties is provided.
Abstract: Voltage-gated calcium (Ca(2+)) channels are key transducers of membrane potential changes into intracellular Ca(2+) transients that initiate many physiological events. There are ten members of the voltage-gated Ca(2+) channel family in mammals, and they serve distinct roles in cellular signal transduction. The Ca(V)1 subfamily initiates contraction, secretion, regulation of gene expression, integration of synaptic input in neurons, and synaptic transmission at ribbon synapses in specialized sensory cells. The Ca(V)2 subfamily is primarily responsible for initiation of synaptic transmission at fast synapses. The Ca(V)3 subfamily is important for repetitive firing of action potentials in rhythmically firing cells such as cardiac myocytes and thalamic neurons. This article presents the molecular relationships and physiological functions of these Ca(2+) channel proteins and provides information on their molecular, genetic, physiological, and pharmacological properties.
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Abstract: Astrocytes are neural cells of ectodermal, neuroepithelial origin that provide for homeostasis and defense of the central nervous system (CNS). Astrocytes are highly heterogeneous in morphological appearance; they express a multitude of receptors, channels, and membrane transporters. This complement underlies their remarkable adaptive plasticity that defines the functional maintenance of the CNS in development and aging. Astrocytes are tightly integrated into neural networks and act within the context of neural tissue; astrocytes control homeostasis of the CNS at all levels of organization from molecular to the whole organ.
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TL;DR: Pharmacological target deconvolution of ketamine and its metabolites will provide insight critical to the development of new pharmacotherapies that possess the desirable clinical effects of ketamines, but limit undesirable side effects.
Abstract: Ketamine, a racemic mixture consisting of (S)- and (R)-ketamine, has been in clinical use since 1970. Although best characterized for its dissociative anesthetic properties, ketamine also exerts analgesic, anti-inflammatory, and antidepressant actions. We provide a comprehensive review of these therapeutic uses, emphasizing drug dose, route of administration, and the time course of these effects. Dissociative, psychotomimetic, cognitive, and peripheral side effects associated with short-term or prolonged exposure, as well as recreational ketamine use, are also discussed. We further describe ketamine’s pharmacokinetics, including its rapid and extensive metabolism to norketamine, dehydronorketamine, hydroxyketamine, and hydroxynorketamine (HNK) metabolites. Whereas the anesthetic and analgesic properties of ketamine are generally attributed to direct ketamine-induced inhibition of N-methyl-D-aspartate receptors, other putative lower-affinity pharmacological targets of ketamine include, but are not limited to, γ-amynobutyric acid (GABA), dopamine, serotonin, sigma, opioid, and cholinergic receptors, as well as voltage-gated sodium and hyperpolarization-activated cyclic nucleotide-gated channels. We examine the evidence supporting the relevance of these targets of ketamine and its metabolites to the clinical effects of the drug. Ketamine metabolites may have broader clinical relevance than was previously considered, given that HNK metabolites have antidepressant efficacy in preclinical studies. Overall, pharmacological target deconvolution of ketamine and its metabolites will provide insight critical to the development of new pharmacotherapies that possess the desirable clinical effects of ketamine, but limit undesirable side effects.
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Additional excerpts
...4 (Catterall, 2011)....
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TL;DR: It is shown that cardiac macrophages facilitate electrical conduction through the distal atrioventricular node, where conducting cells densely intersperse with elongated macrophage expressing connexin 43.
610 citations
Cites background from "Voltage-Gated Calcium Channels"
...While depolarization of the resting membrane potential in working cardiomyocytes can impair excitation and conduction due to sodium channel inactivation, depolarization of AV nodal cells depends chiefly on calcium channels, which have less prominent voltage-dependent inactivation (Catterall, 2011)....
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TL;DR: The mechanisms underlying the function of ion channels and transporters in lymphocytes and innate immune cells are reviewed and their roles in lymphocyte development, adaptive and innateimmune responses, and autoimmunity are discussed, as well as recent efforts to develop pharmacological inhibitors of ions for immunomodulatory therapy.
Abstract: Ion channels and transporters mediate the transport of charged ions across hydrophobic lipid membranes. In immune cells, divalent cations such as calcium, magnesium, and zinc have important roles as second messengers to regulate intracellular signaling pathways. By contrast, monovalent cations such as sodium and potassium mainly regulate the membrane potential, which indirectly controls the influx of calcium and immune cell signaling. Studies investigating human patients with mutations in ion channels and transporters, analysis of gene-targeted mice, or pharmacological experiments with ion channel inhibitors have revealed important roles of ionic signals in lymphocyte development and in innate and adaptive immune responses. We here review the mechanisms underlying the function of ion channels and transporters in lymphocytes and innate immune cells and discuss their roles in lymphocyte development, adaptive and innate immune responses, and autoimmunity, as well as recent efforts to develop pharmacological inhibitors of ion channels for immunomodulatory therapy.
468 citations
Cites background from "Voltage-Gated Calcium Channels"
...They are grouped into three subfamilies (CaV1, CaV2, CaV3) that contain 10 pore-forming α subunits and many associated regulatory β, γ, and δ subunits (67)....
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TL;DR: The focus of this review is on neuronal Ca2+ signaling and its involvement in synaptic signaling processes, neuronal energy metabolism, and neurotransmission, and the contribution of altered Ca2- signaling in the most important neurological disorders will be considered.
Abstract: Calcium (Ca(2+)) is an universal second messenger that regulates the most important activities of all eukaryotic cells. It is of critical importance to neurons as it participates in the transmission of the depolarizing signal and contributes to synaptic activity. Neurons have thus developed extensive and intricate Ca(2+) signaling pathways to couple the Ca(2+) signal to their biochemical machinery. Ca(2+) influx into neurons occurs through plasma membrane receptors and voltage-dependent ion channels. The release of Ca(2+) from the intracellular stores, such as the endoplasmic reticulum, by intracellular channels also contributes to the elevation of cytosolic Ca(2+). Inside the cell, Ca(2+) is controlled by the buffering action of cytosolic Ca(2+)-binding proteins and by its uptake and release by mitochondria. The uptake of Ca(2+) in the mitochondrial matrix stimulates the citric acid cycle, thus enhancing ATP production and the removal of Ca(2+) from the cytosol by the ATP-driven pumps in the endoplasmic reticulum and the plasma membrane. A Na(+)/Ca(2+) exchanger in the plasma membrane also participates in the control of neuronal Ca(2+). The impaired ability of neurons to maintain an adequate energy level may impact Ca(2+) signaling: this occurs during aging and in neurodegenerative disease processes. The focus of this review is on neuronal Ca(2+) signaling and its involvement in synaptic signaling processes, neuronal energy metabolism, and neurotransmission. The contribution of altered Ca(2+) signaling in the most important neurological disorders will then be considered.
447 citations
Cites background from "Voltage-Gated Calcium Channels"
...The Cav3 subfamily is responsible for the T-type current and is important for the pacemaking and repetitive firing of action potentials in cardiac myocytes and thalamic neurons [10]....
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References
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TL;DR: This issue of Pharmacological Reviews includes a new venture in the collaboration between the International Union of Pharmacology (IUPHAR) and the American Society for Pharmacology and Experimental Therapeutics (ASPET), in that a new classification of voltage-gated ion channels is outlined.
Abstract: This issue of Pharmacological Reviews includes a new venture in the collaboration between the International Union of Pharmacology (IUPHAR) and the American Society for Pharmacology and Experimental Therapeutics (ASPET), in that a new classification of voltage-gated ion channels is outlined in this
7,389 citations
TL;DR: Of the ions involved in the intricate workings of the heart, calcium is considered perhaps the most important and spatial microdomains within the cell are important in localizing the molecular players that orchestrate cardiac function.
Abstract: Of the ions involved in the intricate workings of the heart, calcium is considered perhaps the most important. It is crucial to the very process that enables the chambers of the heart to contract and relax, a process called excitation-contraction coupling. It is important to understand in quantitative detail exactly how calcium is moved around the various organelles of the myocyte in order to bring about excitation-contraction coupling if we are to understand the basic physiology of heart function. Furthermore, spatial microdomains within the cell are important in localizing the molecular players that orchestrate cardiac function.
4,216 citations
"Voltage-Gated Calcium Channels" refers background in this paper
...2 channels triggers activation of the RyR2 and initiates Ca2þ-induced Ca2þ-release, activation of actomyosin, and contraction (Fabiato 1983; Bers 2002)....
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...2 channels, Ca 2þ release via RyR, and Ca2þ uptake into the sarcoplasmic reticulum by SERCA Ca2þ pumps—are tightly regulated by second messenger signaling networks (Bers 2002)....
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...…smooth muscle cells, activation of Ca2þ channels initiates contraction directly by increasing cytosolic Ca2þ concentration and indirectly by activating calcium-dependent calcium release by ryanodine-sensitive Ca2þ release channels in the sarcoplasmic reticulum (Reuter 1979; Tsien 1983; Bers 2002)....
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...…During Embryonic2+Visualization of Ca Sarah E. Webb and Andrew L. Miller http://cshperspectives.cshlp.org/cgi/collection/ For additional articles in this collection, see Copyright © 2011 Cold Spring Harbor Laboratory Press; all rights reserved http://cshperspectives.cshlp.org/cgi/collection/…...
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TL;DR: The distinct structures and patterns of regulation of these three families of Ca(2+) channels provide a flexible array of Ca('s 2+) entry pathways in response to changes in membrane potential and a range of possibilities for regulation of Ca (2+) entry by second messenger pathways and interacting proteins.
Abstract: Voltage-gated Ca(2+) channels mediate Ca(2+) entry into cells in response to membrane depolarization. Electrophysiological studies reveal different Ca(2+) currents designated L-, N-, P-, Q-, R-, and T-type. The high-voltage-activated Ca(2+) channels that have been characterized biochemically are complexes of a pore-forming alpha1 subunit of approximately 190-250 kDa; a transmembrane, disulfide-linked complex of alpha2 and delta subunits; an intracellular beta subunit; and in some cases a transmembrane gamma subunit. Ten alpha1 subunits, four alpha2delta complexes, four beta subunits, and two gamma subunits are known. The Cav1 family of alpha1 subunits conduct L-type Ca(2+) currents, which initiate muscle contraction, endocrine secretion, and gene transcription, and are regulated primarily by second messenger-activated protein phosphorylation pathways. The Cav2 family of alpha1 subunits conduct N-type, P/Q-type, and R-type Ca(2+) currents, which initiate rapid synaptic transmission and are regulated primarily by direct interaction with G proteins and SNARE proteins and secondarily by protein phosphorylation. The Cav3 family of alpha1 subunits conduct T-type Ca(2+) currents, which are activated and inactivated more rapidly and at more negative membrane potentials than other Ca(2+) current types. The distinct structures and patterns of regulation of these three families of Ca(2+) channels provide a flexible array of Ca(2+) entry pathways in response to changes in membrane potential and a range of possibilities for regulation of Ca(2+) entry by second messenger pathways and interacting proteins.
2,330 citations
"Voltage-Gated Calcium Channels" refers background in this paper
...Intensive studies of the structure and function of the related pore-forming subunits of Naþ, Ca2þ, and Kþ channels have led to identification of their principal functional domains (reviewed in Catterall 2000a,b; Yi and Jan 2000; Bichet et al. 2003; Yu et al. 2005)....
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TL;DR: Insight into how Munc18-1 collaborates with SNARE proteins in fusion, how the vesicular Ca2+ sensor synaptotagmin 1 triggers fast release, and how thevesicular Rab3 protein regulates release by binding to the active zone proteins RIM1 alpha and RIM2 alpha has advanced the understanding of neurotransmitter release.
Abstract: ▪ Abstract Neurotransmitter release is mediated by exocytosis of synaptic vesicles at the presynaptic active zone of nerve terminals. To support rapid and repeated rounds of release, synaptic vesicles undergo a trafficking cycle. The focal point of the vesicle cycle is Ca2+-triggered exocytosis that is followed by different routes of endocytosis and recycling. Recycling then leads to the docking and priming of the vesicles for another round of exo- and endocytosis. Recent studies have led to a better definition than previously available of how Ca2+ triggers exocytosis and how vesicles recycle. In particular, insight into how Munc18-1 collaborates with SNARE proteins in fusion, how the vesicular Ca2+ sensor synaptotagmin 1 triggers fast release, and how the vesicular Rab3 protein regulates release by binding to the active zone proteins RIM1α and RIM2α has advanced our understanding of neurotransmitter release. The present review attempts to relate these molecular data with physiological results in an emerg...
2,269 citations
"Voltage-Gated Calcium Channels" refers background in this paper
...…entry through voltage-gated Ca2þ channels initiates exocytosis by triggering the fusion of secretory vesicle membranes with the plasma membrane through actions on the SNARE protein complex of syntaxin, SNAP-25, and VAMP/ synaptobrevin (reviewed in Bajjalieh and Scheller 1995; Sudhof 1995, 2004)....
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TL;DR: Evidence is reported for the coexistence of three types of Ca channel in sensory neurones of the chick dorsal root ganglion and the dihydropyridine Ca agonist Bay K 8644 strongly increases the opening probability of L-, but not T- or N-type channels.
Abstract: How many types of calcium channels exist in neurones? This question is fundamental to understanding how calcium entry contributes to diverse neuronal functions such as transmitter release, neurite extension, spike initiation and rhythmic firing. There is considerable evidence for the presence of more than one type of Ca conductance in neurones and other cells. However, little is known about single-channel properties of diverse neuronal Ca channels, or their responsiveness to dihydropyridines, compounds widely used as labels in Ca channel purification. Here we report evidence for the coexistence of three types of Ca channel in sensory neurones of the chick dorsal root ganglion. In addition to a large conductance channel that contributes long-lasting current at strong depolarizations (L), and a relatively tiny conductance that underlies a transient current activated at weak depolarizations (T), we find a third type of unitary activity (N) that is neither T nor L. N-type Ca channels require strongly negative potentials for complete removal of inactivation (unlike L) and strong depolarizations for activation (unlike T). The dihydropyridine Ca agonist Bay K 8644 strongly increases the opening probability of L-, but not T- or N-type channels.
2,204 citations
"Voltage-Gated Calcium Channels" refers background or result in this paper
...In neurons, dopamine and other neurotransmitters inhibit T-type Ca2þ currents via a pathway that is specific for the Gb2 subunit (Wolfe et al. 2003)....
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...T-type Ca2þ currents are mediated by the CaV3 Ca 2þ channels (PerezReyes et al. 1998)....
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...N-type Ca2þ currents were initially distinguished by their intermediate voltage dependence and rate of inactivation—more negative and faster than L-type but more positive and slower than T-type (Nowycky et al. 1985)....
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...Whole-cell voltage clamp and singlechannel recording from dissociated dorsal root ganglion neurons revealed an additional Ca2þ current, N-type (Table 1) (Nowycky et al. 1985)....
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...These results reveal a surprising structural dichotomy between the T-type, low-voltageactivated Ca2þ channels and the high-voltageactivated Ca2þ channels....
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