Mitochondrial Ca2+ antagonist binding sites are associated with an inner mitochondrial membrane anion channel.
The inner mitochondrial membrane contains specific Ca2+ antagonist binding sites unrelated to the L-type Ca2+ channel. The mitochondrial 1,4-dihydropyridine (DHP) and phenylalkylamine sites are reciprocally allosterically coupled, require anions (e.g., Cl-, No3-) for optimal binding, and are inhibited by purine and pyrimidine nucleotides in a noncompetitive manner. In mitochondrial swelling experiments, a concentration-dependent inhibition of an inner mitochondrial membrane anion channel (IMAC) by Ca2+ antagonists from different chemical classes can be demonstrated. Under the conditions of the swelling experiments, affinity of different Ca2+ antagonists and amiodarone, a known IMAC inhibitor, for the mitochondrial (+/-)-[3H]nitrendipine binding site (Kd, 7.2 +/- 2.0 microM; Bmax, 1.03 +/- 0.37 nmol/mg of protein) strongly correlated with their inhibitory potency for the IMAC. Linear regression of pIC50 values for IMAC-induced swelling versus pIC50 values for (+/-)-[3H]nitrendipine binding inhibition yielded a correlation coefficient of 0.91 for all tested DHPs (n = 12, p less than 0.001). Amiodarone inhibited (+/-)-[3H]nitrendipine binding and IMAC-induced swelling with pIC50 values of 6.11 and 5.93, respectively. The correlation coefficient between binding and inhibition of IMAC-induced swelling for amiodarone and all tested Ca2+ antagonists (including non-DHP compounds) was 0.76 (n = 20, p less than 0.001), with the slopes approaching unity. These results suggest the association of the mitochondrial Ca2+ antagonist binding sites with an IMAC.
Institut für Biochemische Pharmakologie, Universität Innsbruck, Austria.
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G
Zernig
I
I
Graziadei
T
T
Moshammer
C
C
Zech
N
N
Reider
H
H
Glossmann
D000638:Amiodarone / Q000494:pharmacology; D000818:Animals; D001665:Binding Sites; D002121:Calcium Channel Blockers / Q000378:metabolism*; D015220:Calcium Channels; D005260:Female; D006168:Guinea Pigs; D007473:Ion Channels / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D009543:Nifedipine / Q000031:analogs & derivatives / Q000494:pharmacology; D009566:Nitrates / Q000494:pharmacology; D009568:Nitrendipine / Q000378:metabolism; D011978:Receptors, Nicotinic / Q000378:metabolism*
D002121:Calcium Channel Blockers; D015220:Calcium Channels; D007473:Ion Channels; D009566:Nitrates; D011978:Receptors, Nicotinic; C019497:niludipin; D009568:Nitrendipine; D009543:Nifedipine; D000638:Amiodarone