J. Neural Transmission 63, 191-208 (1985) ./ouwm/of /gem~ a'v.n.s'm/ss/am 9 by Springer-Verlag 1985 Benzodiazepine Receptors: Multiple Receptors or Multiple Conformations? W. Sieghart Department of Biochemical Psychiatry, Psychiatrische Universit~itsklinik, Wien, Austria With 1 Figure ReceivedJanuary 31, 1985; revised March 2, 1985 Summary Several lines of evidence from reversible binding studies seem to indi- cate there are at least two "central" benzodiazepine recep3tor subtypes, the BZ1 and BZ2 receptors. Irreversible binding studies, using H-flunitrazepam as a photoaffinity label for benzodiazepine receptors, not only are in perfect agreement with the data from reversible binding studies but extend these studies by identifying Psi, a protein with apparent molecular weight 51,000, as a protein associated with the BZ1 receptor and by suggesting that the BZ 2 receptor might actually consist of several different benzodiazepine recep- tors associated with different and distinct proteins irreversibly labeled by 3H-flunitrazepam. Other reversible binding studies have accumulated indicating the existence of several different conformations of benzodiazepine receptors. Irreversible binding studies support this conclusion and in addition suggest the existence of four different benzodiazepine binding sites within the GABA-benzodiazepine receptor complex. It is therefore hypothesized that there are several different GABA-benzodiazepine receptor subtypes all of which have four distinct benzodiazepine binding sites which can exist in at least three different but freely interconvertible conformations. This hypo- thesis can account for all experimental observations obtained so far and might partially explain the distinct clinical effects of structurally similar benzodiazepines. After the discovery of specific high affinity binding sites for benzodiazepines on brain membranes (Mdhler and Okada, 1977;