title: Calcium ions inhibit the allosteric interaction between the dihydropyridine and phenylalkylamine binding site on the voltage-gated calcium channel in heart sarcolemma but not in skeletal muscle transverse tubules.
abstract: Calcium channel blockers bind with high affinity to sites on the voltage-sensitive Ca2+ channel. Radioligand binding studies with various Ca2+ channel blockers have facilitated identification and characterization of binding sites on the channel structure. In the present study we evaluated the relationship between the binding sites for the Ca2+ channel blockers on the voltage-sensitive Ca2+ channel from rabbit heart sarcolemma and rabbit skeletal muscle transverse tubules. [3H]PN200-110 binds with high affinity to a single population of sites on the voltage-sensitive Ca2+ channel in both rabbit heart sarcolemma and skeletal muscle transverse tubules. [3H]PN200-110 binding was not affected by added Ca2+ whereas EGTA and EDTA noncompetitively inhibited binding in both types of membrane preparations. EDTA was a more potent inhibitor of [3H]PN200-110 binding than EGTA. Diltiazem stimulates the binding of [3H]PN200-110 in a temperature-sensitive manner. Verapamil inhibited binding of [3H]PN200-110 to both types of membrane preparations in a negative manner, although this effect was of a complex nature in skeletal muscle transverse tubules. The negative effect of verapamil on [3H]PN200-110 binding in cardiac muscle was completely reversed by Ca2+. On the other hand, Ca2+ was without effect on the negative cooperativity seen between verapamil and [3H]PN200-110 binding in skeletal muscle transverse tubules. Since Ca2+ did not affect [3H]PN200-110 binding to membranes, we would like to suggest that Ca2+ is modulating the negative effect of verapamil on [3H]PN200-110 binding through a distinct Ca2+ binding site.(ABSTRACT TRUNCATED AT 250 WORDS)
authors.affiliation: Department of Pharmacology, University of Ottawa, Ont., Canada.
authors.forename: B J
authors.initials: BJ
authors.lastname: Murphy
authors.forename: B S
authors.initials: BS
authors.lastname: Tuana
mesh_terms: D000494:Allosteric Regulation; D000814:Aniline Compounds / Q000378:metabolism*; D000818:Animals; D002118:Calcium / Q000494:pharmacology*; D002121:Calcium Channel Blockers / Q000378:metabolism; D015220:Calcium Channels / Q000378:metabolism*; D006321:Heart / Q000187:drug effects; D066298:In Vitro Techniques; D017275:Isradipine; D007700:Kinetics; D009132:Muscles / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure; D009206:Myocardium / Q000378:metabolism / Q000648:ultrastructure; D009568:Nitrendipine / Q000378:metabolism; D010069:Oxadiazoles / Q000378:metabolism; D011817:Rabbits; D011978:Receptors, Nicotinic / Q000187:drug effects* / Q000378:metabolism*; D012508:Sarcolemma / Q000187:drug effects / Q000378:metabolism*; D014700:Verapamil / Q000378:metabolism / Q000494:pharmacology
chemical_list: D000814:Aniline Compounds; D002121:Calcium Channel Blockers; D015220:Calcium Channels; D010069:Oxadiazoles; D011978:Receptors, Nicotinic; D009568:Nitrendipine; D014700:Verapamil; D002118:Calcium; D017275:Isradipine