Mitochondrial benzodiazepine receptor linked to inner membrane ion channels by nanomolar actions of ligands.
The mitochrondrial benzodiazepine receptor (mBzR) binds a subset of benzodiazepines and isoquinoline carboxamides with nanomolar affinity and consists of the voltage-dependent anion channel, the adenine nucleotide translocator, and an 18-kDa protein. The effect of ligands of the mBzR on two inner mitochondrial membrane channel activities was determined with patch-clamp techniques. The relative inhibitory potencies of the drugs resemble their binding affinities for the mBzR. Ro5-4864 and protoporphyrin IX inhibit activity of the multiple conductance channel (MCC) and the mitochondrial centum-picosiemen (mCtS) channel activities at nanomolar concentrations. PK11195 inhibits mCtS activity at similar levels. Higher concentrations of protoporphyrin IX induce MCC but possibly not mCtS activity. Clonazepam, which has low affinity for mBzR, is at least 500 times less potent at both channel activities. Ro15-1788, which also has a low mBzR affinity, inhibits MCC at very high concentrations (16 microM). The findings indicate an association of these two channel activities with the proteins forming the mBzR complex and are consistent with an interaction of inner and outer membrane channels.
Kinnally
K W
KW
Department of Biological Sciences, State University of New York, Albany 12222.
Zorov
D B
DB
Antonenko
Y N
YN
Snyder
S H
SH
McEnery
M W
MW
Tedeschi
H
H
D000818:Animals; D001570:Benzodiazepinones / Q000494:pharmacology*; D002998:Clonazepam / Q000494:pharmacology*; D003292:Convulsants / Q000494:pharmacology*; D005442:Flumazenil / Q000494:pharmacology; D007425:Intracellular Membranes / Q000187:drug effects / Q000502:physiology*; D007473:Ion Channels / Q000187:drug effects / Q000502:physiology*; D007546:Isoquinolines / Q000494:pharmacology*; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D008929:Mitochondria, Heart / Q000187:drug effects / Q000502:physiology*; D011524:Protoporphyrins / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011963:Receptors, GABA-A / Q000187:drug effects / Q000502:physiology*; D013367:Submitochondrial Particles / Q000187:drug effects / Q000502:physiology*
D001570:Benzodiazepinones; D003292:Convulsants; D007473:Ion Channels; D007546:Isoquinolines; D011524:Protoporphyrins; D011963:Receptors, GABA-A; C028513:4'-chlorodiazepam; D005442:Flumazenil; D002998:Clonazepam; C028025:protoporphyrin IX; C037850:PK 11195