Review

Authors: Gerald W Zamponi, Joerg Striessnig, Alexandra Koschak...

Voltage-gated calcium channels are required for many key functions in the body. In this review, the different subtypes of voltage-gated calcium channels are described and their physiologic roles and pharmacology are outlined. We describe the current uses of drugs interacting with the different calcium channel subtypes and subunits, as well as specific areas in which there is strong potential for future drug development. Current therapeutic agents include drugs targeting L-type Ca(V)1.2 calcium channels, particularly 1,4-dihydropyridines, which are widely used in the treatment of hypertension. T-type (Ca(V)3) channels are a target of ethosuximide, widely used in absence epilepsy. The auxiliary subunit α2δ-1 is the therapeutic target of the gabapentinoid drugs, which are of value in certain epilepsies and chronic neuropathic pain. The limited use of intrathecal ziconotide, a peptide blocker of N-type (Ca(V)2.2) calcium channels, as a treatment of intractable pain, gives an indication that these channels represent excellent drug targets for various pain conditions. We describe how selectivity for different subtypes of calcium channels (e.g., Ca(V)1.2 and Ca(V)1.3 L-type channels) may be achieved in the future by exploiting differences between channel isoforms in terms of sequence and biophysical properties, variation in splicing in different target tissues, and differences in the properties of the target tissues themselves in terms of membrane potential or firing frequency. Thus, use-dependent blockers of the different isoforms could selectively block calcium channels in particular pathologies, such as nociceptive neurons in pain states or in epileptic brain circuits. Of important future potential are selective Ca(V)1.3 blockers for neuropsychiatric diseases, neuroprotection in Parkinson's disease, and resistant hypertension. In addition, selective or nonselective T-type channel blockers are considered potential therapeutic targets in epilepsy, pain, obesity, sleep, and anxiety. Use-dependent N-type calcium channel blockers are likely to be of therapeutic use in chronic pain conditions. Thus, more selective calcium channel blockers hold promise for therapeutic intervention.

Topics: Calcium Channel Blockers; Calcium Channels; Calcium Channels, L-Type; Calcium Channels, N-Type; Calcium Channels, T-Type; Cardiovascular Diseases; Cyclic AMP-Dependent Protein Kinases; GTP-Binding Proteins; Hearing Disorders; Humans; Metabolic Diseases; Nervous System Diseases; Night Blindness; Phospholipids; Receptor Protein-Tyrosine Kinases

PubMed: 26362469
DOI: 10.1124/pr.114.009654

Review

Authors: Evanthia Nanou, William A Catterall

Voltage-gated calcium channels couple depolarization of the cell-surface membrane to entry of calcium, which triggers secretion, contraction, neurotransmission, gene expression, and other physiological responses. They are encoded by ten genes, which generate three voltage-gated calcium channel subfamilies: Ca1; Ca2; and Ca3. At synapses, Ca2 channels form large signaling complexes in the presynaptic nerve terminal, which are responsible for the calcium entry that triggers neurotransmitter release and short-term presynaptic plasticity. Ca1 channels form signaling complexes in postsynaptic dendrites and dendritic spines, where their calcium entry induces long-term potentiation. These calcium channels are the targets of mutations and polymorphisms that alter their function and/or regulation and cause neuropsychiatric diseases, including migraine headache, cerebellar ataxia, autism, schizophrenia, bipolar disorder, and depression. This article reviews the molecular properties of calcium channels, considers their multiple roles in synaptic plasticity, and discusses their potential involvement in this wide range of neuropsychiatric diseases.

Topics: Animals; Calcium Channels; Calcium Signaling; Humans; Mental Disorders; Mutation; Neuronal Plasticity; Protein Structure, Secondary

PubMed: 29723500
DOI: 10.1016/j.neuron.2018.03.017

Review

Authors: William A Catterall

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.

Topics: Animals; Calcium Channel Blockers; Calcium Channels; Calcium Signaling; Excitation Contraction Coupling; Humans; Models, Biological; Protein Structure, Quaternary; Protein Structure, Tertiary; Synaptic Transmission

PubMed: 21746798
DOI: 10.1101/cshperspect.a003947

Review

Authors: Brett A Simms, Gerald W Zamponi

Voltage-gated calcium channels are the primary mediators of depolarization-induced calcium entry into neurons. There is great diversity of calcium channel subtypes due to multiple genes that encode calcium channel α1 subunits, coassembly with a variety of ancillary calcium channel subunits, and alternative splicing. This allows these channels to fulfill highly specialized roles in specific neuronal subtypes and at particular subcellular loci. While calcium channels are of critical importance to brain function, their inappropriate expression or dysfunction gives rise to a variety of neurological disorders, including, pain, epilepsy, migraine, and ataxia. This Review discusses salient aspects of voltage-gated calcium channel function, physiology, and pathophysiology.

Topics: Animals; Brain Diseases; Calcium Channels; Humans; Neurons

PubMed: 24698266
DOI: 10.1016/j.neuron.2014.03.016

Review

Authors: V Nimmrich, A Eckert

Degenerative dementia is mainly caused by Alzheimer's disease and/or cerebrovascular abnormalities. Disturbance of the intracellular calcium homeostasis is central to the pathophysiology of neurodegeneration. In Alzheimer's disease, enhanced calcium load may be brought about by extracellular accumulation of amyloid-β. Recent studies suggest that soluble forms facilitate influx through calcium-conducting ion channels in the plasma membrane, leading to excitotoxic neurodegeneration. Calcium channel blockade attenuates amyloid-β-induced neuronal decline in vitro and is neuroprotective in animal models. Vascular dementia, on the other hand, is caused by cerebral hypoperfusion and may benefit from calcium channel blockade due to relaxation of the cerebral vasculature. Several calcium channel blockers have been tested in clinical trials of dementia and the outcome is heterogeneous. Nimodipine as well as nilvadipine prevent cognitive decline in some trials, whereas other calcium channel blockers failed. In trials with a positive outcome, BP reduction did not seem to play a role in preventing dementia, indicating a direct protecting effect on neurons. An optimization of calcium channel blockers for the treatment of dementia may involve an increase of selectivity for presynaptic calcium channels and an improvement of the affinity to the inactivated state. Novel low molecular weight compounds suitable for proof-of-concept studies are now available.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Brain; Calcium Channel Blockers; Calcium Channels; Calcium Channels, L-Type; Calcium Signaling; Dementia; Disease Progression; Drugs, Investigational; Humans; Neurons; Nootropic Agents; Synaptic Transmission

PubMed: 23638877
DOI: 10.1111/bph.12240

Authors: Elizabeth M Adler

Topics: Animals; Bacteria; Calcium Channels; Cockroaches; Endocytosis; Mechanotransduction, Cellular

PubMed: 23797418
DOI: 10.1085/jgp.201311041

Authors: Gerald W Zamponi, Terrance P Snutch

Topics: Animals; Calcium; Calcium Channels; Humans; Ion Channel Gating

PubMed: 23518035
DOI: 10.1016/j.bbamem.2013.03.014

Review

Authors: Diane Lipscombe, Arturo Andrade

Voltage-gated calcium ion channels are essential for numerous biological functions of excitable cells and there is wide spread appreciation of their importance as drug targets in the treatment of many disorders including those of cardiovascular and nervous systems. Each Cacna1 gene has the potential to generate a number of structurally, functionally, and in some cases pharmacologically unique CaVα1 subunits through alternative pre-mRNA splicing and the use of alternate promoters. Analyses of rapidly emerging deep sequencing data for a range of human tissue transcriptomes contain information to quantify tissue-specific and alternative exon usage patterns for Cacna1 genes. Cellspecific actions of nuclear DNA and RNA binding proteins control the use of alternate promoters and the selection of alternate exons during pre-mRNA splicing, and they determine the spectrum of protein isoforms expressed within different types of cells. Amino acid compositions within discrete protein domains can differ substantially among CaV isoforms expressed in different tissues, and such differences may be greater than those that exist across CaV channel homologs of closely related species. Here we highlight examples of CaV isoforms that have unique expression patterns and that exhibit different pharmacological sensitivities. Knowledge of expression patterns of CaV isoforms in different human tissues, cell populations, ages, and disease states should inform strategies aimed at developing the next generation of CaV channel inhibitors and agonists with improved tissue-specificity.

Topics: Alternative Splicing; Animals; Calcium Channels; Humans

PubMed: 25966698
DOI: 10.2174/1874467208666150507103215

Review

Authors: Bruno Acuña, Juan Bello-Zepeda, Germán Montenegro...

Pulmonary arterial hypertension is characterized by increased mean pulmonary arterial pressure, resistance, and pathological remodeling of pulmonary arteries. Calcium entry from the extracellular to the intracellular space through voltage-dependent and -independent channels play a major role in the increase of contractility of pulmonary arteries and in the loss of regulation of the proliferative behavior of the cells from the different layers of the pulmonary arterial wall. In doing so, these channels contribute to enhanced vasoconstriction of pulmonary arteries and their pathological remodeling. This review aims to summarize the evidence obtained from animal and cellular models regarding the involvement of the main plasma membrane calcium channels in these key pathophysiological processes for pulmonary arterial hypertension, discussing the potential value as pharmacological targets for therapies in the present and the future.

Topics: Humans; Hypertension, Pulmonary; Calcium Channels; Animals; Calcium Signaling; Calcium Channel Blockers; Signal Transduction; Pulmonary Artery; Vasoconstriction

PubMed: 38801384
DOI: 10.4067/s0034-98872023000600753

Review

Authors: Britany Rufenach, Filip Van Petegem

In skeletal muscle tissue, an intriguing mechanical coupling exists between two ion channels from different membranes: the L-type voltage-gated calcium channel (Ca1.1), located in the plasma membrane, and ryanodine receptor 1 (RyR1) located in the sarcoplasmic reticulum membrane. Excitable cells rely on Cas to initiate Ca entry in response to action potentials. RyRs can amplify this signal by releasing Ca from internal stores. Although this process can be mediated through Ca as a messenger, an overwhelming amount of evidence suggests that RyR1 has recruited Ca1.1 directly as its voltage sensor. The exact mechanisms that underlie this coupling have been enigmatic, but a recent wave of reports have illuminated the coupling protein STAC3 as a critical player. Without STAC3, the mechanical coupling between Ca1.1 and RyR1 is lost, and muscles fail to contract. Various sequence variants of this protein have been linked to congenital myopathy. Other STAC isoforms are expressed in the brain and may serve as regulators of L-type Cas. Despite the short length of STACs, several points of contacts have been proposed between them and Cas. However, it is currently unclear whether STAC3 also forms direct interactions with RyR1, and whether this modulates RyR1 function. In this review, we discuss the 3D architecture of STAC proteins, the biochemical evidence for their interactions, the relevance of these connections for functional modulation, and their involvement in myopathy.

Topics: Adaptor Proteins, Signal Transducing; Animals; Calcium Channels; Excitation Contraction Coupling; Humans; Muscle, Skeletal; src Homology Domains

PubMed: 34129875
DOI: 10.1016/j.jbc.2021.100874