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

Journal Article · Sat Dec 31 23:00:00 EST 1983 · J. Cardiovasc. Pharmacol.; (United States)

DOI:https://doi.org/10.1097/00005344-198406004-00007· OSTI ID:5709909

Glossmann, H; Ferry, D R; Goll, A; Rombusch, M

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.

• Research Organization: Justus Liebig-Universitaet, Giessen, FRG
• OSTI ID: 5709909
• Journal Information: J. Cardiovasc. Pharmacol.; (United States), Journal Name: J. Cardiovasc. Pharmacol.; (United States) Vol. 6 Suppl. 4; ISSN JCPCD
• Country of Publication: United States
• Language: English

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59 BASIC BIOLOGICAL SCIENCES
AFFINITY
ALKALINE EARTH METAL COMPOUNDS
AUTONOMIC NERVOUS SYSTEM AGENTS
BETA DECAY RADIOISOTOPES
BIOCHEMICAL REACTION KINETICS
BODY
BRAIN
CALCIUM COMPOUNDS
CARDIOVASCULAR SYSTEM
CATIONS
CENTRAL NERVOUS SYSTEM
CHARGED PARTICLES
CHEMICAL BONDS
COMPARATIVE EVALUATIONS
DAYS LIVING RADIOISOTOPES
DRUGS
ELECTRON CAPTURE RADIOISOTOPES
HALOGEN COMPOUNDS
HEART
INTERMEDIATE MASS NUCLEI
IODINE 125
IODINE COMPOUNDS
IODINE ISOTOPES
IONS
ISOTOPES
KINETICS
LABELLED COMPOUNDS
LIGANDS
METALLOPROTEINS
NERVOUS SYSTEM
NUCLEI
ODD-EVEN NUCLEI
ORGANIC COMPOUNDS
ORGANS
PHARMACOLOGY
PROTEINS
RADIOISOTOPES
REACTION KINETICS
RECEPTORS
SKELETON
STOICHIOMETRY
SYMPATHOLYTICS
TRITIUM COMPOUNDS