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William A Catterall - One of the best experts on this subject based on the ideXlab platform.
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structure and pharmacology of voltage gated sodium and Calcium Channels
Annual Review of Pharmacology and Toxicology, 2020Co-Authors: William A Catterall, Michael J Lenaeus, Tamer Gamal M EldinAbstract:Voltage-gated sodium and Calcium Channels are evolutionarily related transmembrane signaling proteins that initiate action potentials, neurotransmission, excitation-contraction coupling, and other physiological processes. Genetic or acquired dysfunction of these proteins causes numerous diseases, termed channelopathies, and sodium and Calcium Channels are the molecular targets for several major classes of drugs. Recent advances in the structural biology of these proteins using X-ray crystallography and cryo-electron microscopy have given new insights into the molecular basis for their function and pharmacology. Here we review this recent literature and integrate findings on sodium and Calcium Channels to reveal the structural basis for their voltage-dependent activation, fast and slow inactivation, ion conductance and selectivity, and complex pharmacology at the atomic level. We conclude with the theme that new understanding of the diseases and therapeutics of these Channels will be derived from application of the emerging structural principles from these recent structural analyses.
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structural basis for pharmacology of voltage gated sodium and Calcium Channels
Molecular Pharmacology, 2015Co-Authors: William A Catterall, T M SwansonAbstract:Voltage-gated sodium Channels initiate action potentials in nerve, muscle, and other electrically excitable cells. Voltage-gated Calcium Channels are activated by depolarization during action potentials, and Calcium influx through them is the key second messenger of electrical signaling, initiating secretion, contraction, neurotransmission, gene transcription, and many other intracellular processes. Drugs that block sodium Channels are used in local anesthesia and the treatment of epilepsy, bipolar disorder, chronic pain, and cardiac arrhythmia. Drugs that block Calcium Channels are used in the treatment of epilepsy, chronic pain, and cardiovascular disorders, including hypertension, angina pectoris, and cardiac arrhythmia. The principal pore-forming subunits of voltage-gated sodium and Calcium Channels are structurally related and likely to have evolved from ancestral voltage-gated sodium Channels that are widely expressed in prokaryotes. Determination of the structure of a bacterial ancestor of voltage-gated sodium and Calcium Channels at high resolution now provides a three-dimensional view of the binding sites for drugs acting on sodium and Calcium Channels. In this minireview, we outline the different classes of sodium and Calcium channel drugs, review studies that have identified amino acid residues that are required for their binding and therapeutic actions, and illustrate how the analogs of those key amino acid residues may form drug-binding sites in three-dimensional models derived from bacterial Channels.
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international union of pharmacology xl compendium of voltage gated ion Channels Calcium Channels
Pharmacological Reviews, 2003Co-Authors: William A Catterall, Terrance P. Snutch, Joerg Striessnig, Edward PerezreyesAbstract: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/.
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ca2 calmodulin binds to and modulates p q type Calcium Channels
Nature, 1999Co-Authors: Amy S Lee, Daniel R Storm, Todd Scheuer, Scott T Wong, Daniel Gallagher, William A CatterallAbstract:Neurotransmitter release at many central synapses is initiated by an influx of Calcium ions through P/Q-type Calcium Channels1,2, which are densely localized in nerve terminals3. Because neurotransmitter release is proportional to the fourth power of Calcium concentration4,5, regulation of its entry can profoundly influence neurotransmission. N- and P/Q-type Calcium Channels are inhibited by G proteins6,7, and recent evidence indicates feedback regulation of P/Q-type Channels by Calcium8. Although Calcium-dependent inactivation of L-type Channels is well documented9,10,11, little is known about how Calcium modulates P/Q-type Channels. Here we report a Calcium-dependent interaction between calmodulin and a novel site in the carboxy-terminal domain of the α1A subunit of P/Q-type Channels. In the presence of low concentrations of intracellular Calcium chelators, Calcium influx through P/Q-type Channels enhances channel inactivation, increases recovery from inactivation and produces a long-lasting facilitation of the Calcium current. These effects are prevented by overexpression of a calmodulin-binding inhibitor peptide and by deletion of the calmodulin-binding domain. Our results reveal an unexpected association of Ca2+/calmodulin with P/Q-type Calcium Channels that may contribute to Calcium-dependent synaptic plasticity.
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identification of a syntaxin binding site on n type Calcium Channels
Neuron, 1994Co-Authors: Zu Hang Sheng, Jens Rettig, Masami Takahashi, William A CatterallAbstract:Summary Immunochemical studies have suggested a tight association of syntaxin with N-type Calcium Channels. Syntaxin specifically interacts with the fusion proteins containing the cytoplasmic loop (L II–III ) between homologous repeats II and III of the α 1 subunit of the class B N-type Calcium channel (α 1B ) from rat brain, but not with those of the class A Q-type (α 1A ) or the class S L-type (α 1S ) Calcium Channels. This interaction is mediated by an 87 amino acid sequence (773–859) containing two overlapping predicted helix-loop-helix domains. The 87 amino acid peptide can specifically block binding of native N-type Calcium Channels to syntaxin, indicating that this binding site is required for stable interaction of these two proteins. Interaction takes place with the C-terminal one-third of syntaxin (residues 181–288), which is thought to be anchored in the presynaptic plasma membrane. Our results suggest a direct interaction between the cytoplasmic domains of these two presynaptic membrane proteins that could have an important role in the targeting and docking of synaptic vesicles near N-type Calcium Channels, enabling tight structural and functional association of Calcium entry sites and neurotransmitter release sites.
Zeynab Hafizibarjin - One of the best experts on this subject based on the ideXlab platform.
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vasodilatory effect of asafoetida essential oil on rat aorta rings the role of nitric oxide prostacyclin and Calcium Channels
Phytomedicine, 2017Co-Authors: Hassan Esmaeili, Mansour Esmailidehaj, Mozhdeh Sharifi, Mohammad Ebrahim Rezvani, Zeynab HafizibarjinAbstract:Abstract Background Asafoetida is an oleo-gum resin mainly obtained from Ferula assa-foetida L. species in the apiaceae family. Previous studies have shown that it has antispasmodic effects on rat's and pig's ileums. Purpose The main goals of this study were to assess the vasodilatory effect of asafoetida essential oil (AEO) on the contractile response of rat's aorta rings and to find the role of nitric oxide, cyclooxygenase, and Calcium Channels. Thoracic aorta rings were stretched under a steady-state tension of 1 g in an organ bath apparatus for 1 h and then precontracted by KCl (80 mM) in the presence and absence of AEO. L-NAME (blocker of nitric oxide synthase) and indomethacin (blocker of cyclooxygenase) were used to assess the role of nitric oxide (NO) and prostacyclin in the vasodilatory effect of AEO. Also, the effect of AEO on the influx of Calcium through the cell membrane Calcium Channels was determined. Results Data showed that AEO had vasodilatory effects on aorta rings with both intact (IC50 = 1.6 µl/l) or denuded endothelium (IC50 = 19.2 µl/l) with a significantly higher potency in intact endothelium rings. The vasodilatory effects of AEO were reduced, but not completely inhibited, in the presence of L-NAME or indomethacin. Adding AEO to the free-Calcium medium also significantly reduced the CaCl2-induced contractions. Conclusion The results indicated that AEO has a potent vasodilatory effect that is endothelium-dependent and endothelium-independent. Also, it reduced the influx of Calcium into the cell through plasma membrane Calcium Channels.
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vasodilatory effect of asafoetida essential oil on rat aorta rings the role of nitric oxide prostacyclin and Calcium Channels
Phytomedicine, 2017Co-Authors: Hassan Esmaeili, Mansour Esmailidehaj, Mozhdeh Sharifi, Mohammad Ebrahim Rezvani, Zeynab HafizibarjinAbstract:Abstract Background Asafoetida is an oleo-gum resin mainly obtained from Ferula assa-foetida L. species in the apiaceae family. Previous studies have shown that it has antispasmodic effects on rat's and pig's ileums. Purpose The main goals of this study were to assess the vasodilatory effect of asafoetida essential oil (AEO) on the contractile response of rat's aorta rings and to find the role of nitric oxide, cyclooxygenase, and Calcium Channels. Thoracic aorta rings were stretched under a steady-state tension of 1 g in an organ bath apparatus for 1 h and then precontracted by KCl (80 mM) in the presence and absence of AEO. L-NAME (blocker of nitric oxide synthase) and indomethacin (blocker of cyclooxygenase) were used to assess the role of nitric oxide (NO) and prostacyclin in the vasodilatory effect of AEO. Also, the effect of AEO on the influx of Calcium through the cell membrane Calcium Channels was determined. Results Data showed that AEO had vasodilatory effects on aorta rings with both intact (IC50 = 1.6 µl/l) or denuded endothelium (IC50 = 19.2 µl/l) with a significantly higher potency in intact endothelium rings. The vasodilatory effects of AEO were reduced, but not completely inhibited, in the presence of L-NAME or indomethacin. Adding AEO to the free-Calcium medium also significantly reduced the CaCl2-induced contractions. Conclusion The results indicated that AEO has a potent vasodilatory effect that is endothelium-dependent and endothelium-independent. Also, it reduced the influx of Calcium into the cell through plasma membrane Calcium Channels.
Bruce P Bean - One of the best experts on this subject based on the ideXlab platform.
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Interactions among Toxins That Inhibit N-type and P-type Calcium Channels
2013Co-Authors: Stefan I Mcdonough, Isabelle M Mintz, Linda M. Bol, Bruce P BeanAbstract:abstract A number of peptide toxins from venoms of spiders and cone snails are high affinity ligands for voltage-gated Calcium Channels and are useful tools for studying Calcium channel function and structure. Using wholecell recordings from rat sympathetic ganglion and cerebellar Purkinje neurons, we studied toxins that target neuronal N-type (Ca V2.2) and P-type (Ca V2.1) Calcium Channels. We asked whether different toxins targeting the same Channels bind to the same or different sites on the channel. Five toxins (�-conotoxin-GVIA, �-conotoxin MVIIC, �-agatoxin-IIIA, �-grammotoxin-SIA, and �-agatoxin-IVA) were applied in pairwise combinations to either N- or P-type Channels. Differences in the characteristics of inhibition, including voltage dependence, reversal kinetics, and fractional inhibition of current, were used to detect additive or mutually occlusive effects of toxins. Results suggest at least two distinct toxin binding sites on the N-type channel and three on the P-type channel. On N-type Channels, results are consistent with blockade of the channel pore by �-CgTx-GVIA, �-Aga-IIIA, and �-CTx-MVIIC, whereas grammotoxin likely binds to a separate region coupled to channel gating. �-Aga-IIIA produces partial channel block by decreasing single-channel conductance. On P-type Channels, �-CTx-MVIIC and �-Aga-IIIA both likely bind near the mouth of the pore. �-Aga-IVA and grammotoxin each bind to distinct regions associated with channel gating that do not overlap with the binding region of pore blockers. For both N- and P-type Channels, �-CTx-MVIIC binding produces complete channel block, but is prevented by previous partial channel block by �-Aga-IIIA
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mibefradil inhibition of t type Calcium Channels in cerebellar purkinje neurons
Molecular Pharmacology, 1998Co-Authors: Stefan I Mcdonough, Bruce P BeanAbstract:The antihypertensive agent mibefradil completely and reversibly inhibited T-type Calcium Channels in freshly isolated rat cerebellar Purkinje neurons. The potency of mibefradil was increased at less hyperpolarized holding potentials, and the apparent affinity was correlated with the degree of channel inactivation. At 35 degrees, the apparent dissociation constant Kapp was 1 microM at a holding voltage of -110 mV (corresponding to noninactivated Channels) and 83 nM at a holding voltage of -70 mV (corresponding to 65% inactivation). The increased affinity was attributable mainly to a decreased off-rate. Mibefradil also inhibited P-type Calcium Channels in Purkinje neurons, but inhibition was much less potent. At a holding potential of -70 mV, the Kapp for mibefradil inhibition of P-type Channels was approximately 200-fold higher than that for inhibition of T-type Channels. Mibefradil should be a useful compound for distinguishing T-type Channels from high voltage-activated Calcium Channels in neurons studied in vitro.
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inhibition of Calcium Channels in rat central and peripheral neurons by omega conotoxin mviic
The Journal of Neuroscience, 1996Co-Authors: Stefan I Mcdonough, Linda M Boland, Isabelle M Mintz, Kenton J. Swartz, Bruce P BeanAbstract:Inhibition of voltage-dependent Calcium Channels by omega-conotoxin MVIIC (omega-CTx-MVIIC) was studied in various types of rat neurons. When studied with 5 mM Ba2+ as charge carrier, omega-CTx-MVIIC block of N-type Calcium Channels in sympathetic neurons was potent, with half- block at 18 nM. Block of N-type Channels had a rapid onset (tau approximately 1 sec at 1 microM omega-CTx-MVIIC) and quick reversibility (tau approximately 30 sec). The rate of block was proportional to toxin concentration, consistent with 1:1 binding of toxin to Channels, with a rate constant (k on) of approximately 1 X 10(6) M-1. sec-1. Both potency and rate of block were reduced dramatically with increasing concentrations of extracellular Ba2+ omega- CTx-MVIIC also blocked P-type Calcium Channels in cerebellar Purkinje neurons, but both development and reversal of block were far slower than for N-type Channels. The rate of block was proportional to toxin concentration, with k on -1.5 x 10(3) M-1. sec-1 at 5 mM Ba2+. From this value and an unblocking time constant of approximately 200 min, a dissociation constant of approximately 50 nM was estimated. Thus, block of P-type Channels is potent but very slow. In hippocampal CA3 pyramidal neurons, omega-CTx-MVIIC blocked approximately 50% of the high-threshold Calcium channel current; one component (approximately 20%) was blocked with the rapid kinetics expected for N-type Channels, whereas the other component was blocked slowly. The component blocked slowly was reduced but not eliminated by preexposure to 200 nM or 1 microM omega-Aga-IVA.
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Structure and properties of omega-agatoxin IVB, a new antagonist of P-type Calcium Channels.
Molecular pharmacology, 1993Co-Authors: Michael E. Adams, Isabelle M Mintz, M.d. Reily, V. Thanabal, Bruce P BeanAbstract:A new peptide antagonist of voltage-activated Calcium Channels was purified from venom of the funnel web spider, Agelenopsis aperta. This 48-amino acid peptide, omega-agatoxin (omega-Aga)-IVB, was found to be a potent (Kd, approximately 3 nM) blocker of P-type Calcium Channels in rat cerebellar Purkinje neurons but had no activity against T-type, L-type, or N-type Calcium Channels in a variety of neurons. The Calcium channel-blocking properties of omega-Aga-IVB were similar to those of another toxin, omega-Aga-IVA, which has 71% amino acid identity with omega-Aga-IVB. The 10-fold greater abundance of omega-Aga-IVB in venom allowed structural studies using NMR spectroscopy. The three-dimensional structure derived from NMR data resulted in a proposed disulfide bond configuration for the peptide. Although omega-Aga-IVB has fewer basic and more acidic residues than does omega-Aga-IVA, the two toxins show conservation of positively charged residues in a mid-peptide region that is predicted to form one face of the omega-Aga-IVB molecule. This region may be crucial for high affinity binding to the P-type Calcium channel. In contrast, the amino termini of the two toxins have different charges and seem unlikely to be involved in binding to the channel.
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p type Calcium Channels blocked by the spider toxin ω aga iva
Nature, 1992Co-Authors: Isabelle M Mintz, Bruce P Bean, V J Venema, Kristine M Swiderek, Terry D Lee, Michael E. AdamsAbstract:VOLTAGE-DEPENDENT Calcium Channels mediate Calcium entry into neurons, which is crucial for many processes in the brain including synaptic transmission, dendritic spiking, gene expression and cell death1–5. Many types of Calcium Channels exist in mam-malian brains6–19, but high-affinity blockers are available for only two types, L-type Channels (targeted by nimodipine and other dihydropyridine channel blockers20–22) and N-type Channels (targeted by ω-conotoxin22–26). In a search for new channel blockers, we have identified a peptide toxin from funnel web spider venom, ω-Aga-IVA, which is a potent inhibitor of both Calcium entry into rat brain synaptosomes and of 'P-type' Calcium Channels8 in rat Purkinje neurons. ω-Aga-IVA will facilitate characterization of brain Calcium Channels resistant to existing channel blockers and may assist in the design of neuroprotective drugs.
Hassan Esmaeili - One of the best experts on this subject based on the ideXlab platform.
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vasodilatory effect of asafoetida essential oil on rat aorta rings the role of nitric oxide prostacyclin and Calcium Channels
Phytomedicine, 2017Co-Authors: Hassan Esmaeili, Mansour Esmailidehaj, Mozhdeh Sharifi, Mohammad Ebrahim Rezvani, Zeynab HafizibarjinAbstract:Abstract Background Asafoetida is an oleo-gum resin mainly obtained from Ferula assa-foetida L. species in the apiaceae family. Previous studies have shown that it has antispasmodic effects on rat's and pig's ileums. Purpose The main goals of this study were to assess the vasodilatory effect of asafoetida essential oil (AEO) on the contractile response of rat's aorta rings and to find the role of nitric oxide, cyclooxygenase, and Calcium Channels. Thoracic aorta rings were stretched under a steady-state tension of 1 g in an organ bath apparatus for 1 h and then precontracted by KCl (80 mM) in the presence and absence of AEO. L-NAME (blocker of nitric oxide synthase) and indomethacin (blocker of cyclooxygenase) were used to assess the role of nitric oxide (NO) and prostacyclin in the vasodilatory effect of AEO. Also, the effect of AEO on the influx of Calcium through the cell membrane Calcium Channels was determined. Results Data showed that AEO had vasodilatory effects on aorta rings with both intact (IC50 = 1.6 µl/l) or denuded endothelium (IC50 = 19.2 µl/l) with a significantly higher potency in intact endothelium rings. The vasodilatory effects of AEO were reduced, but not completely inhibited, in the presence of L-NAME or indomethacin. Adding AEO to the free-Calcium medium also significantly reduced the CaCl2-induced contractions. Conclusion The results indicated that AEO has a potent vasodilatory effect that is endothelium-dependent and endothelium-independent. Also, it reduced the influx of Calcium into the cell through plasma membrane Calcium Channels.
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vasodilatory effect of asafoetida essential oil on rat aorta rings the role of nitric oxide prostacyclin and Calcium Channels
Phytomedicine, 2017Co-Authors: Hassan Esmaeili, Mansour Esmailidehaj, Mozhdeh Sharifi, Mohammad Ebrahim Rezvani, Zeynab HafizibarjinAbstract:Abstract Background Asafoetida is an oleo-gum resin mainly obtained from Ferula assa-foetida L. species in the apiaceae family. Previous studies have shown that it has antispasmodic effects on rat's and pig's ileums. Purpose The main goals of this study were to assess the vasodilatory effect of asafoetida essential oil (AEO) on the contractile response of rat's aorta rings and to find the role of nitric oxide, cyclooxygenase, and Calcium Channels. Thoracic aorta rings were stretched under a steady-state tension of 1 g in an organ bath apparatus for 1 h and then precontracted by KCl (80 mM) in the presence and absence of AEO. L-NAME (blocker of nitric oxide synthase) and indomethacin (blocker of cyclooxygenase) were used to assess the role of nitric oxide (NO) and prostacyclin in the vasodilatory effect of AEO. Also, the effect of AEO on the influx of Calcium through the cell membrane Calcium Channels was determined. Results Data showed that AEO had vasodilatory effects on aorta rings with both intact (IC50 = 1.6 µl/l) or denuded endothelium (IC50 = 19.2 µl/l) with a significantly higher potency in intact endothelium rings. The vasodilatory effects of AEO were reduced, but not completely inhibited, in the presence of L-NAME or indomethacin. Adding AEO to the free-Calcium medium also significantly reduced the CaCl2-induced contractions. Conclusion The results indicated that AEO has a potent vasodilatory effect that is endothelium-dependent and endothelium-independent. Also, it reduced the influx of Calcium into the cell through plasma membrane Calcium Channels.
Kenton J. Swartz - One of the best experts on this subject based on the ideXlab platform.
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Inhibition of T-type voltage-gated Calcium Channels by a new scorpion toxin.
Nature Neuroscience, 1998Co-Authors: Rosalind S-i. Chuang, Howard Jaffe, Leanne L. Cribbs, Edward Perez-reyes, Kenton J. SwartzAbstract:The biophysical properties of T-type voltage-gated Calcium Channels are well suited to pacemaking and to supporting Calcium flux near the resting membrane potential in both excitable and non-excitable cells. We have identified a new scorpion toxin (kurtoxin) that binds to the α 1G T-type Calcium channel with high affinity and inhibits the channel by modifying voltage-dependent gating. This toxin distinguishes between α 1G T-type Calcium Channels and other types of voltage-gated Calcium Channels, including α 1A , α 1B , α 1C and α 1E . Like the other α-scorpion toxins to which it is related, kurtoxin also interacts with voltage-gated sodium Channels and slows their inactivation. Kurtoxin will facilitate characterization of the subunit composition of T-type Calcium Channels and help determine their involvement in electrical and biochemical signaling.
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inhibition of Calcium Channels in rat central and peripheral neurons by omega conotoxin mviic
The Journal of Neuroscience, 1996Co-Authors: Stefan I Mcdonough, Linda M Boland, Isabelle M Mintz, Kenton J. Swartz, Bruce P BeanAbstract:Inhibition of voltage-dependent Calcium Channels by omega-conotoxin MVIIC (omega-CTx-MVIIC) was studied in various types of rat neurons. When studied with 5 mM Ba2+ as charge carrier, omega-CTx-MVIIC block of N-type Calcium Channels in sympathetic neurons was potent, with half- block at 18 nM. Block of N-type Channels had a rapid onset (tau approximately 1 sec at 1 microM omega-CTx-MVIIC) and quick reversibility (tau approximately 30 sec). The rate of block was proportional to toxin concentration, consistent with 1:1 binding of toxin to Channels, with a rate constant (k on) of approximately 1 X 10(6) M-1. sec-1. Both potency and rate of block were reduced dramatically with increasing concentrations of extracellular Ba2+ omega- CTx-MVIIC also blocked P-type Calcium Channels in cerebellar Purkinje neurons, but both development and reversal of block were far slower than for N-type Channels. The rate of block was proportional to toxin concentration, with k on -1.5 x 10(3) M-1. sec-1 at 5 mM Ba2+. From this value and an unblocking time constant of approximately 200 min, a dissociation constant of approximately 50 nM was estimated. Thus, block of P-type Channels is potent but very slow. In hippocampal CA3 pyramidal neurons, omega-CTx-MVIIC blocked approximately 50% of the high-threshold Calcium channel current; one component (approximately 20%) was blocked with the rapid kinetics expected for N-type Channels, whereas the other component was blocked slowly. The component blocked slowly was reduced but not eliminated by preexposure to 200 nM or 1 microM omega-Aga-IVA.