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Title: Molecular pharmacology of the calcium channel: evidence for subtypes, multiple drug-receptor sites, channel subunits, and the development of a radioiodinated 1,4-dihydropyridine calcium channel label, (/sup 125/I)iodipine

Abstract

Radiolabeled Ca2+ antagonists (1,4-dihydropyridines, verapamil, and D-cis-diltiazem) were used to study voltage-operated Ca2+ channels in different excitable tissues. The concept of three subtypes of Ca2+ channels, represented by brain, heart, and skeletal-muscle isoreceptors for 1,4-dihydropyridines, is developed. The three subtypes are characterized by a variety of criteria. Despite the biochemical differences between the subtypes, they have the same Mr in situ by target-size analysis (Mr approximately equal to 180,000, when evaluated by (/sub 3/H)nimodipine). The concept of the metalloprotein nature of the channel and the interaction of channel drugs with the Me2+ binding sites of the ionic pore is demonstrated. Distinct but interacting drug-receptor sites of the Ca2+ channel are found by direct labeling as well as indirectly by drug competition studies. The authors distinguish between the 1,4-dihydropyridine site, the verapamil site, and the D-cis-diltiazem site. Each receptor site can exist in high and low-affinity state; the distribution of receptor sites in these states is regulated by temperature, ions, and drugs. The concept of intrinsic activity of drugs to stabilize the high-affinity state is exemplified for the 1,4-dihydropyridines. A change in the channel architecture is induced by binding of D-cis-diltiazem to its drug receptor site. This is proven by target-sizemore » analysis of the channel in situ. Partially purified t-tubule membranes from skeletal muscle are an extremely rich source of Ca2+ channel drug-receptor sites. The stoichiometry was determined in this preparation and found to be four verapamil:two 1,4-dihydropyridine:one D-cis-diltiazem site. A novel Ca2+ channel probe, (/sup 125/I)iodipine (2,200 Ci/mmol), was synthetized, and the properties of this ligand are presented.« less

Authors:
; ; ;
Publication Date:
Research Org.:
Justus Liebig-Universitaet, Giessen, FRG
OSTI Identifier:
5709909
Resource Type:
Journal Article
Resource Relation:
Journal Name: J. Cardiovasc. Pharmacol.; (United States); Journal Volume: 6 Suppl. 4
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; CALCIUM COMPOUNDS; BIOCHEMICAL REACTION KINETICS; RECEPTORS; SYMPATHOLYTICS; AFFINITY; BRAIN; CATIONS; CHEMICAL BONDS; COMPARATIVE EVALUATIONS; HEART; IODINE 125; IODINE COMPOUNDS; LIGANDS; METALLOPROTEINS; PHARMACOLOGY; SKELETON; STOICHIOMETRY; TRITIUM COMPOUNDS; ALKALINE EARTH METAL COMPOUNDS; AUTONOMIC NERVOUS SYSTEM AGENTS; BETA DECAY RADIOISOTOPES; BODY; CARDIOVASCULAR SYSTEM; CENTRAL NERVOUS SYSTEM; CHARGED PARTICLES; DAYS LIVING RADIOISOTOPES; DRUGS; ELECTRON CAPTURE RADIOISOTOPES; HALOGEN COMPOUNDS; INTERMEDIATE MASS NUCLEI; IODINE ISOTOPES; IONS; ISOTOPES; KINETICS; LABELLED COMPOUNDS; NERVOUS SYSTEM; NUCLEI; ODD-EVEN NUCLEI; ORGANIC COMPOUNDS; ORGANS; PROTEINS; RADIOISOTOPES; REACTION KINETICS; 550201* - Biochemistry- Tracer Techniques

Citation Formats

Glossmann, H., Ferry, D.R., Goll, A., and Rombusch, M.. Molecular pharmacology of the calcium channel: evidence for subtypes, multiple drug-receptor sites, channel subunits, and the development of a radioiodinated 1,4-dihydropyridine calcium channel label, (/sup 125/I)iodipine. United States: N. p., 1984. Web. doi:10.1097/00005344-198406004-00007.
Glossmann, H., Ferry, D.R., Goll, A., & Rombusch, M.. Molecular pharmacology of the calcium channel: evidence for subtypes, multiple drug-receptor sites, channel subunits, and the development of a radioiodinated 1,4-dihydropyridine calcium channel label, (/sup 125/I)iodipine. United States. doi:10.1097/00005344-198406004-00007.
Glossmann, H., Ferry, D.R., Goll, A., and Rombusch, M.. Sun . "Molecular pharmacology of the calcium channel: evidence for subtypes, multiple drug-receptor sites, channel subunits, and the development of a radioiodinated 1,4-dihydropyridine calcium channel label, (/sup 125/I)iodipine". United States. doi:10.1097/00005344-198406004-00007.
@article{osti_5709909,
title = {Molecular pharmacology of the calcium channel: evidence for subtypes, multiple drug-receptor sites, channel subunits, and the development of a radioiodinated 1,4-dihydropyridine calcium channel label, (/sup 125/I)iodipine},
author = {Glossmann, H. and Ferry, D.R. and Goll, A. and Rombusch, M.},
abstractNote = {Radiolabeled Ca2+ antagonists (1,4-dihydropyridines, verapamil, and D-cis-diltiazem) were used to study voltage-operated Ca2+ channels in different excitable tissues. The concept of three subtypes of Ca2+ channels, represented by brain, heart, and skeletal-muscle isoreceptors for 1,4-dihydropyridines, is developed. The three subtypes are characterized by a variety of criteria. Despite the biochemical differences between the subtypes, they have the same Mr in situ by target-size analysis (Mr approximately equal to 180,000, when evaluated by (/sub 3/H)nimodipine). The concept of the metalloprotein nature of the channel and the interaction of channel drugs with the Me2+ binding sites of the ionic pore is demonstrated. Distinct but interacting drug-receptor sites of the Ca2+ channel are found by direct labeling as well as indirectly by drug competition studies. The authors distinguish between the 1,4-dihydropyridine site, the verapamil site, and the D-cis-diltiazem site. Each receptor site can exist in high and low-affinity state; the distribution of receptor sites in these states is regulated by temperature, ions, and drugs. The concept of intrinsic activity of drugs to stabilize the high-affinity state is exemplified for the 1,4-dihydropyridines. A change in the channel architecture is induced by binding of D-cis-diltiazem to its drug receptor site. This is proven by target-size analysis of the channel in situ. Partially purified t-tubule membranes from skeletal muscle are an extremely rich source of Ca2+ channel drug-receptor sites. The stoichiometry was determined in this preparation and found to be four verapamil:two 1,4-dihydropyridine:one D-cis-diltiazem site. A novel Ca2+ channel probe, (/sup 125/I)iodipine (2,200 Ci/mmol), was synthetized, and the properties of this ligand are presented.},
doi = {10.1097/00005344-198406004-00007},
journal = {J. Cardiovasc. Pharmacol.; (United States)},
number = ,
volume = 6 Suppl. 4,
place = {United States},
year = {Sun Jan 01 00:00:00 EST 1984},
month = {Sun Jan 01 00:00:00 EST 1984}
}