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Calcium Channel Structure
Published by Anonymous on 2007/9/27 (2194 reads)
1: Med Sci (Paris). 2005 Mar;21(3):279-83.


[Structure of the calcium channel beta subunit: the place of the beta-interaction domain]

[Article in French]

Rousset M, Charnet P, Cens T.

Equipe de Neurobiologie moléculaire, Centre de Recherche de Biochimie macromoléculaire, CNRS FRE 2593, 1919, route de Mende, 34293 Montpellier, France.

Voltage-gated calcium channels are key players in a number of fundamental physiological functions including contraction, secretion, transmitter release or gene activation. They allow a flux of calcium into the cell that constitutes a switch-on signal for most of these functions. The structures responsible for the shaping of these fluxes by the membrane voltage belong to the channel itself, but a number of associated proteins are known to more precisely tune this calcium entry and adapt it to the cellular demand. The calcium channel regulatory beta subunit is undoubtedly the most important one, being influent on the expression, the kinetics, the voltage-dependence of channel opening and closing and on the pharmacology of the channel. Heterologous expression, combined to mutagenesis and electrophysiological and biochemical experiments have revealed the roles of short sequences of the beta subunit, including the BID (beta-interaction domain), in the physical and functional interactions with the channel pore. The resolved crystal structure of the beta subunit now sheds new light on these sequences and their interactions with the rest of the protein. The presence of a type 3 src-homology (SH3) domain and a guanylate kinase (GK) domain confirms that the subunit belongs to the MAGUK protein family. Consistently, the polyproline binding site and the kinase function of the SH3 and the GK domains, respectively, are non functional, and the BID appears to be buried in the structure, preserving the SH3-GK interaction but not directly available for interactions with the channel pore subunit. Anchoring of the beta subunit to the channel occurs via a hydrophobic grove in the GK domain, leaving a large surface of the subunit open to other protein-protein interactions. To what extent the intramolecular SH3-GK interaction is necessary for the stabilisation of this grove in a functional unit remains to be understood. The beta subunit may thus play a key role in scaffolding multiple proteins around the channel and organizing diverse calcium-dependent signalling pathways directly linked to voltage-gated calcium entry. These findings will undoubtedly vitalize the search for new beta-specific partners and functions.

Publication Types:
English Abstract
Review

PMID: 15745702 [PubMed - indexed for MEDLINE]

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2: Curr Med Chem Cardiovasc Hematol Agents. 2003 Jun;1(2):113-41.


New advances in the field of calcium channel antagonists: cardiovascular effects and structure-activity relationships.

Romero M, Sánchez I, Pujol MD.

Laboratori de Química Farmacèutica, Facultat de Farmàcia, Universitat de Barcelona, Av Diagonal 643, 08028-Barcelona, Spain.

In the last 15 years, calcium channel blockers have been widely used for treating cardiovascular diseases. These agents are a heterogeneous group of drugs with differing cardiovascular effects, and are effective in the treatment of angina and hypertension. These synthetic compounds bind separately with receptor sites located in or near the calcium channel, at molecular sites still to be fully identified. Verapamil, nifedipine and diltiazem are the most representative calcium channel blockers and used as prototypes for the design and development of new anticalcium molecules with potential efficacy and reduced toxic effects. There are three different types of voltage-operated calcium channels (VOCs): L-type, T-type and N-type, which are considered extra-cellular, but some anti-calcium agents as bepridil possess potential intracellular calcium activity. Many synthetic compounds containing heterocyclic ring in their structures have attracted considerable interest since current studies revealed their mechanisms and sites of action. This article reviews the new advances in the calcium channel antagonist group, showing new structures with longer-acting and higher vascular selectivity.

Publication Types:
Review

PMID: 15320693 [PubMed - indexed for MEDLINE]

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3: Nippon Naika Gakkai Zasshi. 1998 Apr 10;87(4):678-84.


[Paraneoplastic neurologic syndromes. 2. Lambert-Eaton myasthenic syndrome. 1) The molecular structure of calcium channel and immunology]

[Article in Japanese]

Komai K, Iwasa K, Takamori M.

Publication Types:
Review

PMID: 9627477 [PubMed - indexed for MEDLINE]

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4: Biochem Soc Trans. 1994 May;22(2):492-6.


Subunit structure and phosphorylation of the cardiac L-type calcium channel.

Norman RI, Leach RN.

Department of Medicine, University of Leicester, Leicester Royal Infirmary, U.K.

Publication Types:
Research Support, Non-U.S. Gov't
Review

PMID: 7958352 [PubMed - indexed for MEDLINE]

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5: 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]

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6: Gen Physiol Biophys. 1990 Aug;9(4):321-9.


The dihydropyridine-sensitive calcium channel of the skeletal muscle: biochemistry and structure.

Nastainczyk W, Ludwig A, Hofmann F.

Institut für Medizinische Biochemie, Medizinische Fakultät, Universität des Saarlandes, Homburg, Federal Republic of Germany.

The dihydropyridine-sensitive calcium channel of the rabbit skeletal muscle is the first voltage-gated calcium channel which has been purified and biochemically characterized. The alpha 1-subunit, a 165 kDa protein, of the purified dihydropyridine receptor contains all regulatory sites of a L-type calcium channel and the calcium conducting unit. The purpose of this review is to summarize and discuss recent findings on the structure and possible function of the skeletal muscle calcium channel subunits.

Publication Types:
Review

PMID: 2177019 [PubMed - indexed for MEDLINE]

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7: 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]

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8: Adv Exp Med Biol. 1990;269:73-7.


Structure of the calcium release channel of skeletal muscle sarcoplasmic reticulum and its regulation by calcium.

Lai FA, Meissner G.

Department of Biochemistry, University of North Carolina, School of Medicine, Chapel Hill 27599.

Publication Types:
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.
Review

PMID: 2162136 [PubMed - indexed for MEDLINE]

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9: 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]

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10: Trends Neurosci. 1988 Mar;11(3):90-2.


New insights into the molecular structure of the dihydropyridine-sensitive calcium channel.

Froehner SC.

Publication Types:
News
Review

PMID: 2465612 [PubMed - indexed for MEDLINE]

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11: Ann N Y Acad Sci. 1988;522:134-49.


Molecular properties of structure and regulation of the calcium channel.

Lazdunski M, Barhanin J, Borsotto M, Cognard C, Cooper C, Coppola T, Fosset M, Galizzi JP, Hosey MM, Mourre C, et al.

Biochemistry Center, National Center for Scientific Research, Nice, France.

Publication Types:
Research Support, Non-U.S. Gov't
Review

PMID: 2454048 [PubMed - indexed for MEDLINE]
 

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