Calcium Channel Function
Published by Anonymous on 2007/9/27 (1899 reads)
1: Pharmacol Ther. 2005 Jun;106(3):347-55.
Mouse models to study L-type calcium channel function.
Moosmang S, Lenhardt P, Haider N, Hofmann F, Wegener JW.
Institut für Pharmakologie, Technische Universität München, Biedersteiner Strasse 29, 80802, München, Germany. moosmang@ipt.med.tu-muenchen.de
Calcium influx through voltage gated L-type Ca2+ channels has evolved as one of the most widely used transmembrane signalling mechanisms in eukaryotic organisms. Although pharmacological inhibitors of L-type Ca2+ channels have an important place in medical therapy, the full therapeutic potential of the 4 L-type Ca2+ channel subtypes has not been explored yet. To dissect the physiological relevance of the L-type Ca2+ channel subtype diversity, gene-targeted mouse models carrying deletions of these channels ("knockout mice") have been generated. This review focuses on recent data from studies in mice lacking the Ca(v)1.2 and Ca(v)1.3 pore subunits, which have elucidated some of the roles of L-type Ca2+ channels as mediators of signalling between cell membrane and intracellular processes like blood pressure regulation, smooth muscle contractility, insulin secretion, cardiac development, and learning and memory.
Publication Types:
Review
PMID: 15922017 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
2: J Bioenerg Biomembr. 2003 Dec;35(6):639-47.
Calcium channel alpha2delta subunits: differential expression, function, and drug binding.
Klugbauer N, Marais E, Hofmann F.
Institut für Pharmakologie und Toxikologie, Technische Universität München, Bíedersteiner Str. 29, 80802 München, Germany. klugbauer@ipt.med.tu-muenchen.de
Voltage-activated calcium channels are transmembrane proteins that act as transducers of electrical signals into numerous intracellular activities. On the basis of their electrophysiological properties they are classified as high- and low-voltage-activated calcium channels. High-voltage-activated calcium channels are heterooligomeric proteins consisting of a pore-forming alpha1 subunit and auxiliary alpha2delta, beta, and--in some tissues--gamma subunits. Auxiliary subunits support the membrane trafficking of the alpha1 subunit and modulate the kinetic properties of the channel. In particular, the alpha2delta subunit has been shown to modify the biophysical and pharmacological properties of the alpha1 subunit. The alpha2delta subunit is posttranslationally cleaved to form disulfide-linked alpha2 and, delta proteins, both of which are heavily glycosylated. Recently it was shown that at least four genes encode for alpha2delta subunits which are expressed in a tissue-specific manner. Their biophysical properties were characterized in coexpression studies with high- and low-voltage-activated calcium channels. Mutations in the gene encoding alpha2delta-2 have been found to underlie the ducky phenotype. This mouse mutant is a model for absence epilepsy and is characterized by spike wave seizures and cerebellar ataxia. Alpha2delta subunits can also support pharmacological interactions with drugs that are used for the treatment of epilepsy and neuropathic pain.
Publication Types:
Research Support, Non-U.S. Gov't
Review
PMID: 15000524 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
3: J Bioenerg Biomembr. 2003 Dec;35(6):507-32.
Effects of toxic environmental contaminants on voltage-gated calcium channel function: from past to present.
Atchison WD.
Neuroscience Program, Department of Pharmacology and Toxicology, Michigan State University, East Lansing, Michigan, USA. atchiso1@msu.edu
Voltage-gated Ca2+ channels are targets of the number of naturally occurring toxins, therapeutic agents as well as environmental toxicants. Because of similarities of their chemical structure to Ca2+ in terms of hydrated ionic radius, electron orbital configuration, or other chemical properties, polyvalent cations from aluminum to zinc variously interact with multiple types of voltage-gated Ca2+ channels. These nonphysiological metals have been used to study the structure and function of the Ca2+ channel, especially its permeability characteristics. Two nonphysiological cations, Pb2+ and Hg2+, as well as their organic derivatives, are environmental neurotoxicants which are highly potent Ca2+ channel blockers. These metals also apparently gain intracellular access in part by permeating through Ca2+ channels. In this review the history of Ca2+ channel block produced by Pb2+ and Hg2+ as well as other nonphysiological cations is traced. In particular the characteristics of Ca2+ channel block induced by these environmental neurotoxic metals and the consequences of this action for neuronal function are discussed.
Publication Types:
Research Support, U.S. Gov't, P.H.S.
Review
PMID: 15000519 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
4: Postepy Hig Med Dosw. 2000;54(3):381-90.
[Regulation of potassium channel function in T lymphocytes by intracellular second messengers for calcium, cyclic AMP and membrane lipid metabolites]
[Article in Polish]
Teisseyre A.
Katedra i Zakład Biofizyki Akademii Medycznej we Wrocławiu.
This review focuses on the influence of well-known intracellular second messengers on the activity of potassium channels expressed in human T lymphocytes. Basic biophysical properties of the channels are briefly presented. Available data on the regulatory role of intracellular calcium and cyclic AMP is reviewed. Finally, a possible influence of lipid compounds, especially high-density lipoproteins, lysophospholipids and sphingolipids, on the expression and activity of potassium channels in human T lymphocytes is discussed.
Publication Types:
English Abstract
Research Support, Non-U.S. Gov't
Review
PMID: 10941272 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
5: J Hypertens Suppl. 1998 Sep;16(4):S27-32.
Renal function in noninsulin-dependent diabetes mellitus patients treated with angiotensin-converting enzyme inhibitors and calcium channel blockers.
Nosadini R, Brocco E, Saller A, Cernigoi AM, Abaterusso C, Bortoloso E, Dalla Vestra M, Maioli M, Piarulli F, Fioretto P.
Department of Internal Medicine, University of Padova, Italy.
BACKGROUND: Data have not shown consistent effects with calcium channel blockers on the course of renal function in patients with noninsulin-dependent diabetes mellitus (NIDDM) who have hypertension alone or in association with renal damage. The differences between the antiproteinuric effects of subclasses or formulations of calcium channel blockers and the heterogeneity of renal lesions may contribute to the discrepancy in these data. Clinical studies conducted by the authors and other recent data that describe the course of renal dysfunction in hypertensive NIDDM patients treated with antihypertensive agents are reviewed. Renal structural changes were also evaluated. RESULTS: Most available data indicate that angiotensin-converting enzyme inhibitors and dihydropyridine and nondihydropyridine calcium channel blockers produce similar effects on glomerular filtration rate. In one study of patients achieving intensified, strict control of blood pressure (target<140/85 mmHg) with either cilazapril or amlodipine, glomerular filtration rate declined by 2.03+/-0.66 ml/ min/1.73 m2 per year and 2.01+/-0.71 ml/min/1.73 m2 per year, respectively, in the subgroup with normoalbuminuria and by 2.15+/-0.69 ml/min/1.73 m2 per year and 2.33+/-0.83 ml/min/ 1.73 m2 per year, respectively, in the subgroup with microalbuminuria. Renal lesions in NIDDM patients were found to be structurally heterogeneous and glomerular filtration rate appeared to decline only in patients with renal structural changes typical of NIDDM. CONCLUSIONS: The extent of blood pressure control, rather than the method by which this is accomplished, is the most important factor in determining the evolution of incipient nephropathy in hypertensive NIDDM. The kidneys of microalbuminuric NIDDM patients are structurally heterogeneous with less than one-third of patients having 'typical' diabetic nephropathology.
Publication Types:
Research Support, Non-U.S. Gov't
Review
PMID: 9817189 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
6: J Mol Cell Cardiol. 1998 Oct;30(10):1899-916.
L-type calcium channel abundance and function with cardiac hypertrophy and failure: a review.
Mukherjee R, Spinale FG.
Division of Cardiothoracic Surgery, Department of Surgery, Medical University of South Carolina, Charleston, SC, USA.
Calcium (Ca2+) influx through the L-type Ca2+ channels in cardiac myocytes is the initiating event in the excitation-contraction coupling process. In addition, augmentation of Ca2+ entry through the l-type Ca2+ channels is one means by which beta-adrenergic receptor stimulation increases the inotropic state of the myocyte. The purpose of this review is to summarize data with respect tol-type Ca2+ channel abundance and function in the setting of cardiac hypertrophy and congestive heart failure (CHF). Results from 54 studies on animal models of hypertrophy and heart failure and seven clinical studies of end-stage CHF have been included. In general, the development of severe hypertrophy and CHF in animal models is associated with abnormalities inl-type Ca2+ channel abundance and function. However, in these animal models, abnormalities inl-type Ca2+ channel function do not consistently manifest in milder forms of cardiac pathologies. Alterations inl-type Ca2+ channel function with end-stage human CHF remain equivocal. Nevertheless, in clinical studies as well as animal models,beta-adrenergic receptor mediated augmentation of L-type Ca2+ currents has been demonstrated to be reduced, in general, with hypertrophy and CHF. Future studies that examine the role of the L-type Ca2+ channel with respect to the excitation-contraction coupling process and myocyte contractility are warranted. Copyright 1998 Academic Press
Publication Types:
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.
Review
PMID: 9799645 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
7: Nephrol Dial Transplant. 1997 Nov;12(11):2244-50.
Comment in:
Nephrol Dial Transplant. 1998 May;13(5):1315-6.
Nephrol Dial Transplant. 1998 Sep;13(9):2415-6.
Preservation of renal function: the spectrum of effects by calcium-channel blockers.
Tarif N, Bakris GL.
Nephrology Division, University of Illinois Medical Center at Chicago, USA.
The vast majority of animal data derived from models of either remnant kidney or diabetes demonstrate that dihydropyridine (nifedipine-like) calcium-channel blockers (DHPCCBs) effectively reduce arterial pressure but do not significantly affect proteinuria nor prevent development of glomerular scarring. Conversely, the non-DHPCCBs such as diltiazem and verapamil blunt both the rise in proteinuria as well as mesangial matrix expansion and subsequent glomerular scarring in diabetes. Additionally, the non-DHPCCBs markedly attenuate development of glomerular scarring in the remnant kidney model. The primary reasons for these differences between subclasses of CCBs relates to a lack of the following attributes by DHPCCBs: (1) they fail to reduce glomerular membrane permeability which is increased in these models; (2) they fail to affect the synthesis of certain key matrix proteins that perpetuate development of glomerular scarring (this effect may be due to the differential expression of calcium channels within the glomerular mesangium); and (3) the DHPCCBs totally abolish renal autoregulation in these models, an effect not observed with non-DHPCCBs. Taken together with long-term (> 3 year) clinical studies, primarily in diabetic nephropathy, it is clear that the non-DHPCCBs seem to offer protection to the kidney not available with DHPCCBs alone, unless systolic arterial pressure is reduced to levels of < or = 110 mmHg.
Publication Types:
Review
PMID: 9394306 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
8: Pharmacol Rev. 1992 Sep;44(3):363-76.
Classification of calcium channels and the sites of action of drugs modifying channel function.
Spedding M, Paoletti R.
Syntex Research Centre, Riccarton, Edinburgh, Scotland.
Publication Types:
Review
PMID: 1332082 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
9: J Cardiovasc Pharmacol. 1991;18 Suppl 10:S1-6.
Calcium-channel drugs: structure-function relationships and selectivity of action.
Triggle DJ.
School of Pharmacy, State University of New York, Buffalo 14260.
Calcium channels are ubiquitously distributed in excitable cells. The calcium-channel antagonists interact specifically at the L subclass of channels to mediate cardiovascular effects. These channels may be considered as pharmacologic receptors with specific drug binding sites and subject to a variety of regulatory influences. Each site is specific for agents of the three principal structural classes--the phenylalkylamines, the 1,4-dihydropyridines, and the benzothiazepines--and each exhibits defined structure-activity relationships. The 1,4-dihydropyridine structure exhibits both potent antagonistic and activator properties. The calcium channel antagonists exhibit considerable selectivity of action in the cardiovascular system, both between and within structural groups. This selectivity has a variety of causes including voltage dependence of the interaction, whereby the apparent affinity of the antagonist is determined by the membrane potential and stimulus pattern. Experimental evidence underlying the structure-activity relationships and the voltage-dependent behavior of 1,4-dihydropyridines is reviewed.
Publication Types:
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.
Review
PMID: 1724996 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
10: Gen Physiol Biophys. 1990 Oct;9(5):433-43.
Modulation of calcium channel function in nerve cell membrane.
Kostyuk PG, Doroshenko PA.
A. A. Bogomoletz Institute of Physiology, Acad. Sci. of the Ukr. SSR, Kiev.
Publication Types:
Review
PMID: 2176631 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
11: Seikagaku. 1990 Aug;62(8):1003-19.
[Structure and function of the receptor for calcium channel blockers from skeletal muscle]
[Article in Japanese]
Tanabe T.
Department of Medical Chemistry, Kyoto University Faculty of Medicine.
Publication Types:
Review
PMID: 1700804 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
12: Annu Rev Med. 1990;41:289-302.
Effects of calcium channel blockers on renal function.
Chan L, Schrier RW.
Department of Medicine, University of Colorado School of Medicine, Denver 80262.
Calcium channel or entry blockers (CEBs) exert important vascular and tubular effects on the kidney. These renal effects include an enhancement of glomerular filtration rate (GFR), renal blood flow (RBF), and electrolyte excretion. Experimental studies in animals and humans indicate the potential therapeutic use of CEBs in several important clinical situations, for example attenuating the course of acute renal failure and slowing the progression of chronic renal failure. The latter effect appears to involve both the agent's antihypertensive effect and an additional cytoprotective effect. That CEBs help preserve renal function in renal transplantation has been shown in both animals and humans. In this setting, the effects of cyclosporine (CsA) and CEB on the immune system and on CsA hepatic metabolism are areas of importance for future research.
Publication Types:
Review
PMID: 2184731 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
13: Arzneimittelforschung. 1989 Jan;39(1A):164-8.
[Calcium channels: structure and function of receptors for calcium channel blockers in skeletal muscle]
[Article in German]
Hofmann F, Schneider T, Röhrkasten A, Nastainczyk W, Sieber M, Ruth P, Flockerzi V.
Institut für Physiologische Chemie, Medizinische Fakultät, Universität des Saarlandes, Homburg-Saar.
Calcium channels are important factors in excitation-response coupling. The structure and function of the skeletal muscle receptor for calcium channel antagonists is discussed.
Publication Types:
English Abstract
Research Support, Non-U.S. Gov't
Review
PMID: 2541734 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
14: J Cardiovasc Pharmacol. 1989;14 Suppl 10:S40-51; discussion S59-62.
Antihypertensive drugs and airway function, with special reference to calcium channel blockade.
Löfdahl CG.
Department of Pulmonary Medicine, Renströmska Hospital, Gothenburg University, Sweden.
The treatment of hypertension in patients with airway dysfunction is a delicate problem. This article focuses on the airway effects of some antihypertensive drugs. Early on, the beta-adrenoceptor antagonists were shown to be hazardous in patients with asthma. Nonselective beta-blockers could induce severe asthma attacks and the bronchodilating effect of beta-agonists was totally blocked. Also, the beta-blockers with partial agonist activity totally blocked the effect of bronchodilating beta-agonists. The selective beta 1-adrenoceptor antagonists were shown to have less pronounced effects on the airways, and it was possible to overcome the beta-blockade in the airways with high doses of beta-agonists. beta-Blockers are contraindicated in asthma patients, even if it is possible to give selective beta 1-adrenoceptor antagonists in some patients together with high doses of beta 2-agonists. Angiotensin converting enzyme (ACE)-inhibitors were recently shown to induce cough and bronchial hyperresponsiveness in some patients. This is probably due to an increased inflammation in the bronchial mucosa as substances (e.g., bradykinin) are not metabolized. Therefore, ACE inhibitors could be hazardous in asthmatic patients, as they can increase the underlying bronchial hyperresponsiveness. Calcium channel blockers were earlier considered to be beneficial in asthma, as it was shown that they had a small relaxant effect on bronchial tone, and could amplify the effect of bronchodilators. In studies of provoked bronchoconstriction, calcium channel blockers were shown to have some protective effect against allergens, histamine, methacholine, or exercise-induced bronchoconstriction. Calcium channel blockers do not have a major place in asthma treatment, but as they have no severe side effects on the airways, they could preferably be given to hypertensive patients with airways disease instead of other antihypertensive agents.
Publication Types:
Review
PMID: 2483571 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
15: J Clin Pharm Ther. 1987 Aug;12(4):213-22.
Therapeutic progress--review XXVIII. Platelet function and calcium channel blocking agents.
Greer IA.
Platelets play a major role in the pathogenesis of vascular disorders such as coronary heart disease. The control of platelet function centres on the concentration of free intra-cellular Calcium ions (Ca2+). Increases in intracellular Ca2+ will result in platelet activation and release of substances such as thromboxane A2 which will stimulate further platelet activation and vasoconstriction, leading to vascular damage, thrombosis and ischaemia. Calcium channel blocking agents (CCB's) have the ability to reduce Ca2+ availability and may have potentially beneficial effects on platelet function. CCB's have been convincingly shown to have anti-platelet properties in vitro. They have also shown anti-platelet properties in vivo although this finding has not been consistent. In addition they have been shown to act synergistically with other anti-platelet agents. In the light of the available information it is likely that CCB's have only minor anti-platelet properties in vivo when used alone. Combining CCB's with other anti-platelet agents, however, may allow lower doses of drugs to be used to achieve a satisfactory inhibitory effect on platelet function. Such combination therapy may be of value in the treatment of vascular disorders; however, further studies are required to evaluate these effects in the clinical situation.
Publication Types:
Review
PMID: 3305529 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
16: Acta Pharmacol Toxicol (Copenh). 1986;58 Suppl 2:81-9.
Calcium channel blockade and renal function.
Odar-Cederlöf I.
Since calcium channel blocking agents were introduced into the treatment of hypertension their influence on renal function has become an important issue. In animal experiments calcium channel blocking agents have been shown to increase renal blood flow and glomerular filtration rate and to augment urine flow and electrolyte excretion. In human acute studies the administration of calcium channel blocking agents have elicited similar renal hemodynamic and diuretic effects. Clinical studies on the renal effects of long-term treatment are however still lacking. Studies on the effect on renin release have given divergent results. In acute experiments renin release is increased by calcium channel blocking agents. In long-term treatment, however, no change in peripheral plasma levels of renin has been demonstrated. The influence of decreased renal function on the pharmacokinetics of calcium channel blocking agents has been studied in patients with renal disease. For verapamil the volume of distribution is smaller in uremic patients than in normals and both metabolic and renal clearances are decreased. For nifedipine, on the other hand, similar plasma levels, plasma half life and total plasma clearance are found in uremic patients and normal subjects.
Publication Types:
Review
PMID: 3521200 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
17: Acta Pharmacol Toxicol (Copenh). 1986;58 Suppl 2:91-111.
Calcium, calcium channel blockade and airways function.
Löfdahl CG, Barnes PJ.
This review will highlight recent advances in understanding the physiological role of calcium and effects of calcium channel blockers on pathogenetic factors in asthma, including airway smooth muscle contraction, mast cell degranulation and mucus secretion. A review of clinical studies with calcium channel blockers in asthma will also be presented.
Publication Types:
In Vitro
Review
PMID: 2872771 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
18: Life Sci. 1985 Nov 18;37(20):1843-60.
Modulation of calcium channel function by drugs.
Schramm M, Towart R.
Calcium channel blocking drugs, or "calcium antagonists", have been increasingly used in the last decade, both as valuable cardiovascular drugs, and as tools to investigate the pharmacology of the calcium channels which play a vital role in the excitation-activation coupling of many excitable cells. Three important developments, "patch clamping" to investigate single calcium channels, ligand binding studies to investigate the calcium antagonist "receptor sites", and the introduction of novel calcium channel activators, or "calcium agonists", have recently led to greater understanding of the mechanism of action of drugs on the calcium channel. We show here how the calcium channel modulators interact with the binding sites to increase or decrease calcium flux, and hence to modulate the activity of many excitable tissues. We predict that these new developments will soon result in the isolation of purified calcium channels, and investigation of their subtypes and drug sensitivities. This information could lead to the introduction of novel, more selective calcium antagonists for a variety of indications such as atherosclerosis or neurological disorders. Of particular interest is the potential of tissue-selective calcium agonistic drugs to combat cardiac failure or endocrinological disorders.
Publication Types:
Review
PMID: 2414632 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
19: Am J Cardiol. 1985 Jan 25;55(3):172B-178B.
Effects of calcium-channel blocking agents on left ventricular diastolic function in hypertrophic cardiomyopathy and in coronary artery disease.
Bonow RO.
Abnormal left ventricular (LV) diastolic performance is a characteristic feature of hypertrophic cardiomyopathy (HC) and an important contributor to the development of symptoms. Impaired diastolic filling of the hypertrophied left ventricle results from both diminished distensibility and prolonged or incomplete relaxation. LV distensibility is not only influenced by fixed anatomic abnormalities (such as fibrosis or hypertrophy) that determine the passive elastic properties of the left ventricle, but also is modulated by the dynamics of myocardial relaxation: prolonged or incomplete LV relaxation may restrict the rate and extent of LV filling and result in altered pressure-volume relations throughout diastole. Several studies indicate that impaired LV relaxation and filling in HC may be modified favorably by verapamil or nifedipine administered on a short-term basis in the catheterization laboratory, associated with improved diastolic pressure-volume relations. Verapamil also improves LV filling during oral therapy. Improved indexes of LV filling correlate with symptomatic improvement, both short-term and long-term: Approximately 80% of patients having a persistent increase in peak LV filling rate have persistent improvement in objective exercise tolerance compared with preverapamil values. Altered LV relaxation and filling are also often observed in patients with coronary artery disease (CAD) after myocardial infarction or during acute ischemia. Moreover, impaired filling occurs under resting conditions in many patients who have normal systolic function and no evidence of previous infarction. Nifedipine improves indexes of LV relaxation and distensibility during pacing-induced ischemia and verapamil improves indexes of LV filling at rest and during exercise-induced ischemia.(ABSTRACT TRUNCATED AT 250 WORDS)
Publication Types:
Review
PMID: 3881911 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
20: Am J Cardiol. 1985 Jan 25;55(3):158B-164B.
Influence of calcium-channel blockers on platelet function and arachidonic acid metabolism.
Mehta JL.
Available data indicate that platelet function and arachidonic acid metabolism are important factors in hemostasis and regulation of vascular tone. Plasma membrane and intracellular mobilization of calcium ions are intimately related to platelet activation and release of platelet contents. Release of arachidonic acid from membrane phospholipids as well as subsequent synthesis and release of vasoconstrictor thromboxane A2 are also regulated by movement of calcium ions. Adenosine 3':5'-cyclic phosphate in turn controls levels of free calcium ions in platelets and regulates calcium-dependent reactions. Slow-channel calcium blockers, such as verapamil, diltiazem and nifedipine, inhibit platelet activation in vitro, and decrease platelet adhesion intravascularly. These agents have also been shown to decrease platelet nucleotide release and thromboxane A2 generation. Some preliminary data suggest that calcium blockers also increase generation of vasodilator and platelet antiaggregant prostacyclin, which could contribute to decrease in platelet function. These effects of calcium blockers on platelet function and arachidonic acid metabolism could contribute in part to their efficacy in patients with ischemic heart disease.
Publication Types:
Review
PMID: 2982252 [PubMed - indexed for MEDLINE]
Mouse models to study L-type calcium channel function.
Moosmang S, Lenhardt P, Haider N, Hofmann F, Wegener JW.
Institut für Pharmakologie, Technische Universität München, Biedersteiner Strasse 29, 80802, München, Germany. moosmang@ipt.med.tu-muenchen.de
Calcium influx through voltage gated L-type Ca2+ channels has evolved as one of the most widely used transmembrane signalling mechanisms in eukaryotic organisms. Although pharmacological inhibitors of L-type Ca2+ channels have an important place in medical therapy, the full therapeutic potential of the 4 L-type Ca2+ channel subtypes has not been explored yet. To dissect the physiological relevance of the L-type Ca2+ channel subtype diversity, gene-targeted mouse models carrying deletions of these channels ("knockout mice") have been generated. This review focuses on recent data from studies in mice lacking the Ca(v)1.2 and Ca(v)1.3 pore subunits, which have elucidated some of the roles of L-type Ca2+ channels as mediators of signalling between cell membrane and intracellular processes like blood pressure regulation, smooth muscle contractility, insulin secretion, cardiac development, and learning and memory.
Publication Types:
Review
PMID: 15922017 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
2: J Bioenerg Biomembr. 2003 Dec;35(6):639-47.
Calcium channel alpha2delta subunits: differential expression, function, and drug binding.
Klugbauer N, Marais E, Hofmann F.
Institut für Pharmakologie und Toxikologie, Technische Universität München, Bíedersteiner Str. 29, 80802 München, Germany. klugbauer@ipt.med.tu-muenchen.de
Voltage-activated calcium channels are transmembrane proteins that act as transducers of electrical signals into numerous intracellular activities. On the basis of their electrophysiological properties they are classified as high- and low-voltage-activated calcium channels. High-voltage-activated calcium channels are heterooligomeric proteins consisting of a pore-forming alpha1 subunit and auxiliary alpha2delta, beta, and--in some tissues--gamma subunits. Auxiliary subunits support the membrane trafficking of the alpha1 subunit and modulate the kinetic properties of the channel. In particular, the alpha2delta subunit has been shown to modify the biophysical and pharmacological properties of the alpha1 subunit. The alpha2delta subunit is posttranslationally cleaved to form disulfide-linked alpha2 and, delta proteins, both of which are heavily glycosylated. Recently it was shown that at least four genes encode for alpha2delta subunits which are expressed in a tissue-specific manner. Their biophysical properties were characterized in coexpression studies with high- and low-voltage-activated calcium channels. Mutations in the gene encoding alpha2delta-2 have been found to underlie the ducky phenotype. This mouse mutant is a model for absence epilepsy and is characterized by spike wave seizures and cerebellar ataxia. Alpha2delta subunits can also support pharmacological interactions with drugs that are used for the treatment of epilepsy and neuropathic pain.
Publication Types:
Research Support, Non-U.S. Gov't
Review
PMID: 15000524 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
3: J Bioenerg Biomembr. 2003 Dec;35(6):507-32.
Effects of toxic environmental contaminants on voltage-gated calcium channel function: from past to present.
Atchison WD.
Neuroscience Program, Department of Pharmacology and Toxicology, Michigan State University, East Lansing, Michigan, USA. atchiso1@msu.edu
Voltage-gated Ca2+ channels are targets of the number of naturally occurring toxins, therapeutic agents as well as environmental toxicants. Because of similarities of their chemical structure to Ca2+ in terms of hydrated ionic radius, electron orbital configuration, or other chemical properties, polyvalent cations from aluminum to zinc variously interact with multiple types of voltage-gated Ca2+ channels. These nonphysiological metals have been used to study the structure and function of the Ca2+ channel, especially its permeability characteristics. Two nonphysiological cations, Pb2+ and Hg2+, as well as their organic derivatives, are environmental neurotoxicants which are highly potent Ca2+ channel blockers. These metals also apparently gain intracellular access in part by permeating through Ca2+ channels. In this review the history of Ca2+ channel block produced by Pb2+ and Hg2+ as well as other nonphysiological cations is traced. In particular the characteristics of Ca2+ channel block induced by these environmental neurotoxic metals and the consequences of this action for neuronal function are discussed.
Publication Types:
Research Support, U.S. Gov't, P.H.S.
Review
PMID: 15000519 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
4: Postepy Hig Med Dosw. 2000;54(3):381-90.
[Regulation of potassium channel function in T lymphocytes by intracellular second messengers for calcium, cyclic AMP and membrane lipid metabolites]
[Article in Polish]
Teisseyre A.
Katedra i Zakład Biofizyki Akademii Medycznej we Wrocławiu.
This review focuses on the influence of well-known intracellular second messengers on the activity of potassium channels expressed in human T lymphocytes. Basic biophysical properties of the channels are briefly presented. Available data on the regulatory role of intracellular calcium and cyclic AMP is reviewed. Finally, a possible influence of lipid compounds, especially high-density lipoproteins, lysophospholipids and sphingolipids, on the expression and activity of potassium channels in human T lymphocytes is discussed.
Publication Types:
English Abstract
Research Support, Non-U.S. Gov't
Review
PMID: 10941272 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
5: J Hypertens Suppl. 1998 Sep;16(4):S27-32.
Renal function in noninsulin-dependent diabetes mellitus patients treated with angiotensin-converting enzyme inhibitors and calcium channel blockers.
Nosadini R, Brocco E, Saller A, Cernigoi AM, Abaterusso C, Bortoloso E, Dalla Vestra M, Maioli M, Piarulli F, Fioretto P.
Department of Internal Medicine, University of Padova, Italy.
BACKGROUND: Data have not shown consistent effects with calcium channel blockers on the course of renal function in patients with noninsulin-dependent diabetes mellitus (NIDDM) who have hypertension alone or in association with renal damage. The differences between the antiproteinuric effects of subclasses or formulations of calcium channel blockers and the heterogeneity of renal lesions may contribute to the discrepancy in these data. Clinical studies conducted by the authors and other recent data that describe the course of renal dysfunction in hypertensive NIDDM patients treated with antihypertensive agents are reviewed. Renal structural changes were also evaluated. RESULTS: Most available data indicate that angiotensin-converting enzyme inhibitors and dihydropyridine and nondihydropyridine calcium channel blockers produce similar effects on glomerular filtration rate. In one study of patients achieving intensified, strict control of blood pressure (target<140/85 mmHg) with either cilazapril or amlodipine, glomerular filtration rate declined by 2.03+/-0.66 ml/ min/1.73 m2 per year and 2.01+/-0.71 ml/min/1.73 m2 per year, respectively, in the subgroup with normoalbuminuria and by 2.15+/-0.69 ml/min/1.73 m2 per year and 2.33+/-0.83 ml/min/ 1.73 m2 per year, respectively, in the subgroup with microalbuminuria. Renal lesions in NIDDM patients were found to be structurally heterogeneous and glomerular filtration rate appeared to decline only in patients with renal structural changes typical of NIDDM. CONCLUSIONS: The extent of blood pressure control, rather than the method by which this is accomplished, is the most important factor in determining the evolution of incipient nephropathy in hypertensive NIDDM. The kidneys of microalbuminuric NIDDM patients are structurally heterogeneous with less than one-third of patients having 'typical' diabetic nephropathology.
Publication Types:
Research Support, Non-U.S. Gov't
Review
PMID: 9817189 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
6: J Mol Cell Cardiol. 1998 Oct;30(10):1899-916.
L-type calcium channel abundance and function with cardiac hypertrophy and failure: a review.
Mukherjee R, Spinale FG.
Division of Cardiothoracic Surgery, Department of Surgery, Medical University of South Carolina, Charleston, SC, USA.
Calcium (Ca2+) influx through the L-type Ca2+ channels in cardiac myocytes is the initiating event in the excitation-contraction coupling process. In addition, augmentation of Ca2+ entry through the l-type Ca2+ channels is one means by which beta-adrenergic receptor stimulation increases the inotropic state of the myocyte. The purpose of this review is to summarize data with respect tol-type Ca2+ channel abundance and function in the setting of cardiac hypertrophy and congestive heart failure (CHF). Results from 54 studies on animal models of hypertrophy and heart failure and seven clinical studies of end-stage CHF have been included. In general, the development of severe hypertrophy and CHF in animal models is associated with abnormalities inl-type Ca2+ channel abundance and function. However, in these animal models, abnormalities inl-type Ca2+ channel function do not consistently manifest in milder forms of cardiac pathologies. Alterations inl-type Ca2+ channel function with end-stage human CHF remain equivocal. Nevertheless, in clinical studies as well as animal models,beta-adrenergic receptor mediated augmentation of L-type Ca2+ currents has been demonstrated to be reduced, in general, with hypertrophy and CHF. Future studies that examine the role of the L-type Ca2+ channel with respect to the excitation-contraction coupling process and myocyte contractility are warranted. Copyright 1998 Academic Press
Publication Types:
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.
Review
PMID: 9799645 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
7: Nephrol Dial Transplant. 1997 Nov;12(11):2244-50.
Comment in:
Nephrol Dial Transplant. 1998 May;13(5):1315-6.
Nephrol Dial Transplant. 1998 Sep;13(9):2415-6.
Preservation of renal function: the spectrum of effects by calcium-channel blockers.
Tarif N, Bakris GL.
Nephrology Division, University of Illinois Medical Center at Chicago, USA.
The vast majority of animal data derived from models of either remnant kidney or diabetes demonstrate that dihydropyridine (nifedipine-like) calcium-channel blockers (DHPCCBs) effectively reduce arterial pressure but do not significantly affect proteinuria nor prevent development of glomerular scarring. Conversely, the non-DHPCCBs such as diltiazem and verapamil blunt both the rise in proteinuria as well as mesangial matrix expansion and subsequent glomerular scarring in diabetes. Additionally, the non-DHPCCBs markedly attenuate development of glomerular scarring in the remnant kidney model. The primary reasons for these differences between subclasses of CCBs relates to a lack of the following attributes by DHPCCBs: (1) they fail to reduce glomerular membrane permeability which is increased in these models; (2) they fail to affect the synthesis of certain key matrix proteins that perpetuate development of glomerular scarring (this effect may be due to the differential expression of calcium channels within the glomerular mesangium); and (3) the DHPCCBs totally abolish renal autoregulation in these models, an effect not observed with non-DHPCCBs. Taken together with long-term (> 3 year) clinical studies, primarily in diabetic nephropathy, it is clear that the non-DHPCCBs seem to offer protection to the kidney not available with DHPCCBs alone, unless systolic arterial pressure is reduced to levels of < or = 110 mmHg.
Publication Types:
Review
PMID: 9394306 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
8: Pharmacol Rev. 1992 Sep;44(3):363-76.
Classification of calcium channels and the sites of action of drugs modifying channel function.
Spedding M, Paoletti R.
Syntex Research Centre, Riccarton, Edinburgh, Scotland.
Publication Types:
Review
PMID: 1332082 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
9: J Cardiovasc Pharmacol. 1991;18 Suppl 10:S1-6.
Calcium-channel drugs: structure-function relationships and selectivity of action.
Triggle DJ.
School of Pharmacy, State University of New York, Buffalo 14260.
Calcium channels are ubiquitously distributed in excitable cells. The calcium-channel antagonists interact specifically at the L subclass of channels to mediate cardiovascular effects. These channels may be considered as pharmacologic receptors with specific drug binding sites and subject to a variety of regulatory influences. Each site is specific for agents of the three principal structural classes--the phenylalkylamines, the 1,4-dihydropyridines, and the benzothiazepines--and each exhibits defined structure-activity relationships. The 1,4-dihydropyridine structure exhibits both potent antagonistic and activator properties. The calcium channel antagonists exhibit considerable selectivity of action in the cardiovascular system, both between and within structural groups. This selectivity has a variety of causes including voltage dependence of the interaction, whereby the apparent affinity of the antagonist is determined by the membrane potential and stimulus pattern. Experimental evidence underlying the structure-activity relationships and the voltage-dependent behavior of 1,4-dihydropyridines is reviewed.
Publication Types:
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.
Review
PMID: 1724996 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
10: Gen Physiol Biophys. 1990 Oct;9(5):433-43.
Modulation of calcium channel function in nerve cell membrane.
Kostyuk PG, Doroshenko PA.
A. A. Bogomoletz Institute of Physiology, Acad. Sci. of the Ukr. SSR, Kiev.
Publication Types:
Review
PMID: 2176631 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
11: Seikagaku. 1990 Aug;62(8):1003-19.
[Structure and function of the receptor for calcium channel blockers from skeletal muscle]
[Article in Japanese]
Tanabe T.
Department of Medical Chemistry, Kyoto University Faculty of Medicine.
Publication Types:
Review
PMID: 1700804 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
12: Annu Rev Med. 1990;41:289-302.
Effects of calcium channel blockers on renal function.
Chan L, Schrier RW.
Department of Medicine, University of Colorado School of Medicine, Denver 80262.
Calcium channel or entry blockers (CEBs) exert important vascular and tubular effects on the kidney. These renal effects include an enhancement of glomerular filtration rate (GFR), renal blood flow (RBF), and electrolyte excretion. Experimental studies in animals and humans indicate the potential therapeutic use of CEBs in several important clinical situations, for example attenuating the course of acute renal failure and slowing the progression of chronic renal failure. The latter effect appears to involve both the agent's antihypertensive effect and an additional cytoprotective effect. That CEBs help preserve renal function in renal transplantation has been shown in both animals and humans. In this setting, the effects of cyclosporine (CsA) and CEB on the immune system and on CsA hepatic metabolism are areas of importance for future research.
Publication Types:
Review
PMID: 2184731 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
13: Arzneimittelforschung. 1989 Jan;39(1A):164-8.
[Calcium channels: structure and function of receptors for calcium channel blockers in skeletal muscle]
[Article in German]
Hofmann F, Schneider T, Röhrkasten A, Nastainczyk W, Sieber M, Ruth P, Flockerzi V.
Institut für Physiologische Chemie, Medizinische Fakultät, Universität des Saarlandes, Homburg-Saar.
Calcium channels are important factors in excitation-response coupling. The structure and function of the skeletal muscle receptor for calcium channel antagonists is discussed.
Publication Types:
English Abstract
Research Support, Non-U.S. Gov't
Review
PMID: 2541734 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
14: J Cardiovasc Pharmacol. 1989;14 Suppl 10:S40-51; discussion S59-62.
Antihypertensive drugs and airway function, with special reference to calcium channel blockade.
Löfdahl CG.
Department of Pulmonary Medicine, Renströmska Hospital, Gothenburg University, Sweden.
The treatment of hypertension in patients with airway dysfunction is a delicate problem. This article focuses on the airway effects of some antihypertensive drugs. Early on, the beta-adrenoceptor antagonists were shown to be hazardous in patients with asthma. Nonselective beta-blockers could induce severe asthma attacks and the bronchodilating effect of beta-agonists was totally blocked. Also, the beta-blockers with partial agonist activity totally blocked the effect of bronchodilating beta-agonists. The selective beta 1-adrenoceptor antagonists were shown to have less pronounced effects on the airways, and it was possible to overcome the beta-blockade in the airways with high doses of beta-agonists. beta-Blockers are contraindicated in asthma patients, even if it is possible to give selective beta 1-adrenoceptor antagonists in some patients together with high doses of beta 2-agonists. Angiotensin converting enzyme (ACE)-inhibitors were recently shown to induce cough and bronchial hyperresponsiveness in some patients. This is probably due to an increased inflammation in the bronchial mucosa as substances (e.g., bradykinin) are not metabolized. Therefore, ACE inhibitors could be hazardous in asthmatic patients, as they can increase the underlying bronchial hyperresponsiveness. Calcium channel blockers were earlier considered to be beneficial in asthma, as it was shown that they had a small relaxant effect on bronchial tone, and could amplify the effect of bronchodilators. In studies of provoked bronchoconstriction, calcium channel blockers were shown to have some protective effect against allergens, histamine, methacholine, or exercise-induced bronchoconstriction. Calcium channel blockers do not have a major place in asthma treatment, but as they have no severe side effects on the airways, they could preferably be given to hypertensive patients with airways disease instead of other antihypertensive agents.
Publication Types:
Review
PMID: 2483571 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
15: J Clin Pharm Ther. 1987 Aug;12(4):213-22.
Therapeutic progress--review XXVIII. Platelet function and calcium channel blocking agents.
Greer IA.
Platelets play a major role in the pathogenesis of vascular disorders such as coronary heart disease. The control of platelet function centres on the concentration of free intra-cellular Calcium ions (Ca2+). Increases in intracellular Ca2+ will result in platelet activation and release of substances such as thromboxane A2 which will stimulate further platelet activation and vasoconstriction, leading to vascular damage, thrombosis and ischaemia. Calcium channel blocking agents (CCB's) have the ability to reduce Ca2+ availability and may have potentially beneficial effects on platelet function. CCB's have been convincingly shown to have anti-platelet properties in vitro. They have also shown anti-platelet properties in vivo although this finding has not been consistent. In addition they have been shown to act synergistically with other anti-platelet agents. In the light of the available information it is likely that CCB's have only minor anti-platelet properties in vivo when used alone. Combining CCB's with other anti-platelet agents, however, may allow lower doses of drugs to be used to achieve a satisfactory inhibitory effect on platelet function. Such combination therapy may be of value in the treatment of vascular disorders; however, further studies are required to evaluate these effects in the clinical situation.
Publication Types:
Review
PMID: 3305529 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
16: Acta Pharmacol Toxicol (Copenh). 1986;58 Suppl 2:81-9.
Calcium channel blockade and renal function.
Odar-Cederlöf I.
Since calcium channel blocking agents were introduced into the treatment of hypertension their influence on renal function has become an important issue. In animal experiments calcium channel blocking agents have been shown to increase renal blood flow and glomerular filtration rate and to augment urine flow and electrolyte excretion. In human acute studies the administration of calcium channel blocking agents have elicited similar renal hemodynamic and diuretic effects. Clinical studies on the renal effects of long-term treatment are however still lacking. Studies on the effect on renin release have given divergent results. In acute experiments renin release is increased by calcium channel blocking agents. In long-term treatment, however, no change in peripheral plasma levels of renin has been demonstrated. The influence of decreased renal function on the pharmacokinetics of calcium channel blocking agents has been studied in patients with renal disease. For verapamil the volume of distribution is smaller in uremic patients than in normals and both metabolic and renal clearances are decreased. For nifedipine, on the other hand, similar plasma levels, plasma half life and total plasma clearance are found in uremic patients and normal subjects.
Publication Types:
Review
PMID: 3521200 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
17: Acta Pharmacol Toxicol (Copenh). 1986;58 Suppl 2:91-111.
Calcium, calcium channel blockade and airways function.
Löfdahl CG, Barnes PJ.
This review will highlight recent advances in understanding the physiological role of calcium and effects of calcium channel blockers on pathogenetic factors in asthma, including airway smooth muscle contraction, mast cell degranulation and mucus secretion. A review of clinical studies with calcium channel blockers in asthma will also be presented.
Publication Types:
In Vitro
Review
PMID: 2872771 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
18: Life Sci. 1985 Nov 18;37(20):1843-60.
Modulation of calcium channel function by drugs.
Schramm M, Towart R.
Calcium channel blocking drugs, or "calcium antagonists", have been increasingly used in the last decade, both as valuable cardiovascular drugs, and as tools to investigate the pharmacology of the calcium channels which play a vital role in the excitation-activation coupling of many excitable cells. Three important developments, "patch clamping" to investigate single calcium channels, ligand binding studies to investigate the calcium antagonist "receptor sites", and the introduction of novel calcium channel activators, or "calcium agonists", have recently led to greater understanding of the mechanism of action of drugs on the calcium channel. We show here how the calcium channel modulators interact with the binding sites to increase or decrease calcium flux, and hence to modulate the activity of many excitable tissues. We predict that these new developments will soon result in the isolation of purified calcium channels, and investigation of their subtypes and drug sensitivities. This information could lead to the introduction of novel, more selective calcium antagonists for a variety of indications such as atherosclerosis or neurological disorders. Of particular interest is the potential of tissue-selective calcium agonistic drugs to combat cardiac failure or endocrinological disorders.
Publication Types:
Review
PMID: 2414632 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
19: Am J Cardiol. 1985 Jan 25;55(3):172B-178B.
Effects of calcium-channel blocking agents on left ventricular diastolic function in hypertrophic cardiomyopathy and in coronary artery disease.
Bonow RO.
Abnormal left ventricular (LV) diastolic performance is a characteristic feature of hypertrophic cardiomyopathy (HC) and an important contributor to the development of symptoms. Impaired diastolic filling of the hypertrophied left ventricle results from both diminished distensibility and prolonged or incomplete relaxation. LV distensibility is not only influenced by fixed anatomic abnormalities (such as fibrosis or hypertrophy) that determine the passive elastic properties of the left ventricle, but also is modulated by the dynamics of myocardial relaxation: prolonged or incomplete LV relaxation may restrict the rate and extent of LV filling and result in altered pressure-volume relations throughout diastole. Several studies indicate that impaired LV relaxation and filling in HC may be modified favorably by verapamil or nifedipine administered on a short-term basis in the catheterization laboratory, associated with improved diastolic pressure-volume relations. Verapamil also improves LV filling during oral therapy. Improved indexes of LV filling correlate with symptomatic improvement, both short-term and long-term: Approximately 80% of patients having a persistent increase in peak LV filling rate have persistent improvement in objective exercise tolerance compared with preverapamil values. Altered LV relaxation and filling are also often observed in patients with coronary artery disease (CAD) after myocardial infarction or during acute ischemia. Moreover, impaired filling occurs under resting conditions in many patients who have normal systolic function and no evidence of previous infarction. Nifedipine improves indexes of LV relaxation and distensibility during pacing-induced ischemia and verapamil improves indexes of LV filling at rest and during exercise-induced ischemia.(ABSTRACT TRUNCATED AT 250 WORDS)
Publication Types:
Review
PMID: 3881911 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
20: Am J Cardiol. 1985 Jan 25;55(3):158B-164B.
Influence of calcium-channel blockers on platelet function and arachidonic acid metabolism.
Mehta JL.
Available data indicate that platelet function and arachidonic acid metabolism are important factors in hemostasis and regulation of vascular tone. Plasma membrane and intracellular mobilization of calcium ions are intimately related to platelet activation and release of platelet contents. Release of arachidonic acid from membrane phospholipids as well as subsequent synthesis and release of vasoconstrictor thromboxane A2 are also regulated by movement of calcium ions. Adenosine 3':5'-cyclic phosphate in turn controls levels of free calcium ions in platelets and regulates calcium-dependent reactions. Slow-channel calcium blockers, such as verapamil, diltiazem and nifedipine, inhibit platelet activation in vitro, and decrease platelet adhesion intravascularly. These agents have also been shown to decrease platelet nucleotide release and thromboxane A2 generation. Some preliminary data suggest that calcium blockers also increase generation of vasodilator and platelet antiaggregant prostacyclin, which could contribute to decrease in platelet function. These effects of calcium blockers on platelet function and arachidonic acid metabolism could contribute in part to their efficacy in patients with ischemic heart disease.
Publication Types:
Review
PMID: 2982252 [PubMed - indexed for MEDLINE]
| Navigate through the articles | |
Calcium Channel Interactions
|
|
|
|