Heterogeneity of L-type calcium channel alpha 1 subunits: stereoselective discrimination of different populations by the novel 1,4-dihydropyridine B 874-67.
The basic (pKa = 8.49) 1,4-dihydropyridine B 874-67 [[3-(C1R,2S)- 2-methylamino-1-phenylpropyl]-5-methyl-1,4-dihydro-2,6-dimethyl-(4R)-4-( 3-nitrophenyl)pyridine-3,5-dicarboxylate hydrochloride] has unique properties; it can discriminate two populations of alpha 1 subunits in 1,4-dihydropyridine-sensitive calcium channels labeled with the neutral 1,4-dihydropyridine (+)-[3H]PN 200-110. The two populations, which occur in proportions of approximately 2:1 in rabbit skeletal muscle membranes and highly purified calcium channel preparations, differ approximately 20-fold in their affinity. The corresponding diastereomer, B 874-66, and other 1,4-dihydropyridines (neutral, basic, or permanently charged) do not share this property. The two populations were observed at 2 degrees, 22 degrees, and 37 degrees in similar proportions. Heterogeneity was also observed for guinea pig heart membrane calcium channels labeled with (+)-[3H]PN 200-110. Heterotropic allosteric regulators, Ca2+, and Mg2+, but not Ba2+ and Ni2+, abolished the discriminatory activity of B 874-67 at 2 degrees and 22 degrees, regardless of whether binding of the neutral 1,4-dihydropyridine was stimulated or inhibited. It is proposed that the two alpha 1 subunit populations differ with respect to their 1,4-dihydropyridine binding domain. The structural basis for the two populations is unclear but may relate to the functional heterogeneity of membrane-bound and highly purified calcium channel preparations previously observed by others.
Lakitsch
M
M
Institute for Biochemical Pharmacology, University of Innsbruck, Austria.
Knaus
H G
HG
Topar
G
G
Romanin
C
C
Boer
R
R
Flockerzi
D
D
Striessnig
J
J
Schindler
H
H
Hoeltje
H D
HD
Glossmann
H
H
D000494:Allosteric Regulation; D000818:Animals; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D015220:Calcium Channels / Q000187:drug effects*; D002413:Cations, Divalent / Q000494:pharmacology; D004095:Dihydropyridines / Q000494:pharmacology*; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects; D066298:In Vitro Techniques; D008958:Models, Molecular; D009132:Muscles / Q000187:drug effects; D011817:Rabbits; D013237:Stereoisomerism
D002121:Calcium Channel Blockers; D015220:Calcium Channels; D002413:Cations, Divalent; D004095:Dihydropyridines; C079498:B 874-67