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This summary article presents an overview of the molecular relationships among the voltage-gated calcium channels and a standard nomenclature for them, which is derived from the IUPHAR Compendium of Voltage-Gated Ion Channels. The complete Compendium, including data tables for each member of the calcium channel family can be found at http://www.iuphar-db.org/iuphar-ic/.
Incubation of striatal slices with sodium nitroprusside (SNP) or hydroxylamine (HA) for 60 min caused a dose-dependent increase in dopamine (DA) release. This effect was inhibited completely by tetrodotoxin (TTX) (1 microM) if low concentrations of SNP (1 microM) or HA (10 and 100 microM) were tested. Although-higher concentration of SNP (10 and 100 microM) and HA (500 microM) were still effective in stimulating DA release, increases observed under these conditions were less than the values found in the absence of TTX. Verapamil (10 microM), but not omega-conotoxin (100 nM), significantly reduced DA release stimulated by high concentrations of SNP or HA. When verapamil was combined with TTX, moreover, SNP and HA failed to stimulate DA release. If striatal slices were incubated in the presence of nomifensine (10 microM), SNP and HA did not enhance DA release. SNP and HA-induced depletions in tissue DA levels were also protected by nomifensine. Inhibition of guanylate cyclase with 10 microM of methylene blue could not reduce the effects of NO-donors. SNP and HA also failed to alter endogenous glutamate release from striatal slices. Similarly, SNP and HA-induced increases in DA release were not affected by kynurenic acid and MK-801. These results indicate that NO-donors SNP and HA stimulate DA release by facilitating reverse DA transport. This effect seems to be dependent on the activation of both voltage dependent sodium channels and L-type of calcium channels. Results presented here also indicate that neither endogenous glutamate nor guanylate cyclase activation plays an intermediary role in stimulatory effects of NO-donors on DA release from rat striatal slices.
Basic studies as well as short-term clinical trials of the T-channel-selective calcium channel blocker, mibefradil, are reviewed. The compound reduced afterload and was effective for the symptomatic treatment of hypertension and stable angina pectoris. It did not display any relevant negative inotropic or positive chronotropic effect. Mibefradil has been withdrawn by the manufacturer because of drug interaction at the cytochrome P-450 3A4 enzyme. It is hoped that new T-channel-selective calcium channel blockers will be developed to explore further this promising but so far only preliminarily tested therapeutic possibility.
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A patch-clamp study under high hydrostatic pressure was performed by transferring cells or membrane patches into a pressure vessel (Heinemann, S. H., W. Stühmer, and F. Conti, 1987, Proceedings of the National Academy of Sciences, 84:3229-3233). Whole-cell Na currents as well as Ca currents were measured at pressures up to 40 MPa (approximately 400 atm; 1 MPa = 9.87 atm) in bovine adrenal chromaffin cells. Ca currents were found to be independent of pressure within experimental resolution. The mean amplitude and the gating kinetics of Na currents were affected by less than 20% at 10 MPa. This lack of a pronounced effect is surprising since the high-pressure nervous syndrome (HPNS), a disorder at high pressures known to result from impaired nervous transmission, manifests itself at pressures as low as 5 MPa. The results show that ion channels involved in transmission cannot be implicated in HPNS. However, when exocytosis was studied at high pressure by monitoring the cell capacitance (Neher, E., and A. Marty, 1982, Proceedings of the National Academy of Sciences, 79:6712-6716), more drastic effects were seen. The degranulation evoked by dialyzing the cell with 1 microM free Ca2+ could be slowed by a factor of 2 by application of 10 MPa. The same effect was observed for the degranulation of rat peritoneal mast cells stimulated with 40 microM of the GTP analogue GTP-gamma-S. According to these results, the process of exocytosis is the most likely site at which hydrostatic pressure can act to produce nervous disorders. Furthermore, we demonstrate that pressure can be a useful tool in the investigation of other cellular responses, since we were able to separate different steps occurring during exocytosis owing to their different activation volumes.
The biochemical and biophysical features of the voltage-dependent calcium channels, as discovered in vitro by means of radiolabelled drugs, are presented. The concept of distinct but reciprocally allosterically coupled drug receptor domains linked to calcium binding sites is explained. The evidence for the existence of isochannels (and isoreceptors) is reviewed and the voltage-dependence of 1,4-dihydropyridine binding and action is discussed. The structure of the channel is investigated by radiation-inactivation and by photoaffinity labelling. Low affinity binding sites for calcium channel drugs are shown to reside on the nucleoside carrier.
Calcium influx into ciliary membrane vesicles from paramecia was measured by using arsenazo III as metallochromic indicator and as intravesicular calcium trap. Influx was rapid and reversible. In ciliary membrane vesicles from paramecium pawn mutants which lack the voltage-sensitive calcium channel, calcium influx was significantly less than in wild-type paramecia. These data demonstrate that the voltage-dependent calcium channel of paramecia is functional in a cell-free system and available for biochemical studies.
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Calcium entry through presynaptic voltage-gated calcium channels is essential for neurotransmitter release. The two major types of presynaptic calcium channels contain a synaptic protein interaction site that physically interacts with synaptic vesicle release proteins. This is thought to tighten the coupling between the sources of calcium entry and the neurotransmitter release machinery. Conversely, the binding of synaptic proteins to presynaptic calcium channels regulates calcium channel activity. Hence, presynaptic calcium channels act not only as the masters of the synaptic release process, but also as key targets for feedback inhibition.
Voltage-dependent Ca2+ channels are an important pathway for Ca2+ influx in excitable cells. They also represent an important site of action for a therapeutic group of agents, the Ca2+ channel antagonists. These drugs enjoy considerable use in the cardiovascular area including angina, some arrhythmias, hypertension, and peripheral vascular disorders. The voltage-dependent Ca2+ channels exist in a number of subclasses characterized by electrophysiologic, permeation, and pharmacologic criteria. The Ca2+ channel antagonists, including verapamil, nifedipine, and diltiazem, serve to characterize the L channel class. This channel class has been characterized as a pharmacologic receptor, since it possesses specific drug-binding sites for both antagonists and activators and it is regulated by homologous and heterologous influences. The Ca2+ channels of both voltage- and ligand-regulated classes are likely to continue to be major research targets for new drug design and action.
Calcium channels are well known targets for inhibition by G protein-coupled receptors, and multiple forms of inhibition have been described. Here we report a novel mechanism for G protein-mediated modulation of neuronal voltage-dependent calcium channels that involves the destabilization and subsequent removal of calcium channels from the plasma membrane. Imaging experiments in living sensory neurons show that, within seconds of receptor activation, calcium channels are cleared from the membrane and sequestered in clathrin-coated vesicles. Disruption of the L1-CAM-ankyrin B complex with the calcium channel mimics transmitter-induced trafficking of the channels, reduces calcium influx, and decreases exocytosis. Our results suggest that G protein-induced removal of plasma membrane calcium channels is a consequence of disrupting channel-cytoskeleton interactions and might represent a novel mechanism of presynaptic inhibition.
Calcium entry into excitable cells through voltage-gated calcium channels can be influenced by both the rate and pattern of action potentials. We report here that a cloned neuronal alpha 1C L-type calcium channel can be facilitated by positive pre-depolarization. Both calcium and barium were effective as charge carriers in eliciting voltage-dependent facilitation. The induction of facilitation was shown to be independent of intracellular calcium levels, G-protein interaction and the level of phosphatase activity. Facilitation was reduced by the injection of inhibitors of protein kinase A and required the coexpression of a calcium channel beta subunit. In contrast, three neuronal non-L-type calcium channels, alpha 1A, alpha 1B and alpha 1E, were not subject to voltage-dependent facilitation when coexpressed with a beta subunit. The results indicate that the mechanism of neuronal L-type calcium channel facilitation involves the interaction of alpha 1 and beta subunits and is dependent on protein kinase A activity. The selective voltage-dependent modulation of L-type calcium channels is likely to play an important role in neuronal physiology and plasticity.
Calcium channel beta subunits have marked effects on the trafficking and on several of the biophysical properties of all high voltage activated calcium channels. In this article I shall review information on the different genes, on the structure of the beta subunits, and on their differential expression and post-translational modification. Their role in trafficking and assembly of the calcium channel heteromultimer will be described, and I will then review their effects on voltage-dependent and kinetic properties, stressing the differences between palmitoylated beta2a and the other beta subunits. Evidence for effects on calcium channel pharmacology will also be examined. I shall discuss the hypothesis that beta subunits can bind reversibly to calcium channels, and examine their role in the G protein modulation of calcium channels. Finally, I shall describe the consequences of knock-out of different beta subunit genes, and describe evidence for the involvement of beta subunits in disease.
Calcium channels are large, complex membrane proteins that mediate transmembrane calcium currents. At least 2 kinds of calcium channels are found in heart muscle--the transient type and the long-lasting type. Calcium currents are modulated by diverse endogenous and exogenous factors including hormones, catecholamines, and calcium antagonists. Calcium antagonists act preferentially on vascular smooth muscle and have relatively less effect on the calcium channels of heart muscle. Compared with heart muscle, vascular smooth muscle is relatively depolarized, suggesting that vascular smooth muscle cells have predominantly the long-lasting type of calcium currents. The differential binding to different types of calcium channels underlies the clinical efficacy of the calcium antagonists. A drug such as bepridil, which acts preferentially on the coronary vasculature rather than on the peripheral vasculature, dilates the coronary vessels without depressing cardiac contraction, a putative clinical advantage.
Calcium influx through N-type calcium channels mediates synaptic transmission at numerous central synapses and transduces nociceptive information in the spinal dorsal horn. However, the precise role of N-type calcium channels in pain perception is not fully elucidated. To address this issue, we generated and analyzed knockout mice for alpha(1B,) the pore-forming subunit of the N-type calcium channel. Homozygous mutants are viable, fertile, and show normal motor coordination. In small-diameter dorsal root ganglion neurons from mutants the density of calcium channel currents is significantly reduced, which can be accounted for by the abolition of N-type currents. We performed several pain-related behavioral tests using the mutant mice. alpha(1B)-Deficient mice show reduced response to mechanical stimuli in the von Frey test and increased tail flick latency in response to radiant heat, indicating altered spinal reflexes. However, pain response in the hot plate test is normal. In the formalin paw test, the mutant mice exhibit significantly attenuated response in Phase 2, but normal pain behaviors in Phase 1. The response to visceral inflammatory pain caused by acetic acid is also reduced in alpha(1B) knockout mice. These results suggest that the alpha(1B) subunit of N-type calcium channel plays a major role in pain perception by acting at the spinal level, but not at the supraspinal level.
Changes in free intracellular Ca2+ levels provide signals that allow nerve and muscle cells to respond to a host of external stimuli. A major mechanism for elevating the level of intracellular Ca2+ is the influx of extracellular Ca2+ through voltage-dependent channels in the cell membrane. Recent research has yielded new insights into the physiological properties, molecular structure, biochemical regulation, and functional heterogeneity of voltage-dependent Ca2+ channels. In addition, Ca2+ channel antagonist drugs have been developed that are valuable both as probes of channel structure and function and as therapeutic agents. Preliminary evidence suggests that these drugs may be useful in the treatment of diverse neurological disorders, including headache, subarachnoid hemorrhage, stroke, and epilepsy.
Calcium overload of neurons leads to cell death and is a key feature in neurodegenerative diseases. The polycyclic amine NGP1-01 blocks L-type voltage operated calcium channels in cardiomyocytes. Here, we tested whether NGP1-01 blocks neuronal calcium channels. NGP1-01 (1 microM) inhibited depolarization-induced calcium influx by 78% in cortical neurons preloaded with fura-2 AM, with a potency similar to nimodipine. NGP1-01 (1 microM) also inhibited N-methyl-D: -aspartate (NMDA)-induced (1 mM) calcium influx by 52%, only slightly less potent than memantine. Using in vivo-microdialysis, we monitored choline release during NMDA infusion as a measure of excitotoxic membrane breakdown. Intraperitoneal injection of NGP1-01 (40 mg/kg) reduced NMDA-induced membrane breakdown by 31% (P < 0.01) while memantine (10 mg/kg) reduced choline release by 40%. Our results demonstrate that NGP1-01 simultaneously blocks both major neuronal calcium channels and is sufficiently brain-permeable. We conclude that NGP1-01 is a promising lead structure for a new class of dual-mechanism neuroprotective agents.
Calcium channels that are regulated by voltage have an important role in linking cellular stimulation to physiological responses in the nervous system. In addition, a number of autoimmune or genetic disorders that affect calcium channels (channelopathies) have been identified, including several that affect neuromuscular function. These include the Lambert-Eaton myasthenic syndrome, which is associated with autoantibodies directed against neuronal calcium channels, as well as at least two inherited neuromuscular diseases-hypokalemic periodic paralysis and some varieties of malignant hyperthermia-that affect calcium channels in skeletal muscle. Preliminary progress has been achieved in understanding the relationship between these immunological or genetic abnormalities and the alterations in channel function that they produce. A major challenge that remains is to determine how calcium channelopathies lead to the curious assortment of paroxysmal and progressive disorders that are observed clinically.