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Affinity of Compounds for the Benzodiazepine Site (Neurotransmitter/Mutagenesis/Channel/Inhibitory) DOLAN B

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Affinity of Compounds for the Benzodiazepine Site (Neurotransmitter/Mutagenesis/Channel/Inhibitory) DOLAN B Proc. Nati. Acad. Sci. USA Vol. 88, pp. 1421-1425, February 1991 Neurobiology y-Aminobutyric acid type A receptor point mutation increases the affinity of compounds for the benzodiazepine site (neurotransmitter/mutagenesis/channel/inhibitory) DOLAN B. PRITCHETT*tt AND PETER H. SEEBURGt *Departments of Pediatrics and Pharmacology, University of Pennsylvania, Philadelphia, PA 19104; and tLaboratory of Molecular Neuroendocrinology, Center for Molecular Biology, University of Heidelberg, 6900 Heidelberg, Federal Republic of Germany Communicated by Erminio Costa, November 13, 1990 ABSTRACT Recombinantly expressed y-aminobutyric benzodiazepine agonists. The a, subunit imparts high-affinity acid type A (GABAA) receptors consisting of a,, P2, and 72 binding for CL 218872 (15, 19), while a2, a3, and a5 subunits subunits contain a binding site for benzodiazepines that differs create sites with 10-fold lower affinities for this triazolopy- in its properties from that of ac3%2y2 receptors. Amino acid ridozine (8, 15). Several other compounds, including the substitutions between the GABAA receptor a subunits were benzodiazepines quazepam and 2-oxoquazepam (20), the analyzed for their effect on the binding of compounds to the f3-carbolines f8-CCM and 3-CCE (21), and the imidazolpy- benzodiazepine site. By converting ever smaller regions of the ridines zolpidem, alpidem, and AHR-14479 (22, 23) show a3 subunit sequence to that of the a, subunit, we show that a similar pharmacological profiles, with the notable exception single substitution (glycine for glutamic acidj increases the that the three last-named compounds fail to bind to ternary affinity for several compounds approximately 10-fold without receptors containing the a5 subunit (8). changing the affinity for nonselective compounds. Hence, the Since such ternary receptors closely mimic the ligand- identified amino acids may interact directly with the ligand and binding properties and differential localizations of central derme part of the benzodiazepine binding sites in these recep- benzodiazepine sites, one can utilize the well-defined recom- tors. binant receptors to characterize molecular determinants of these clinically important drug targets (6, 15-18). One ap- Benzodiazepines are the most widely prescribed anxiolytics, proach to the study ofreceptor binding and function has been sedatives, muscle relaxants, anticonvulsants, and hypnotics to create chimeric receptors with primary structures derived (1). The benzodiazepines were in clinical use for 15 years from separate receptor subtypes (24). Particular sequence before their site of action was discovered to be the y-ami- changes that alter the binding or signal transduction of the nobutyric acid type A (GABAA) receptor (2). Compounds of, resultant receptor may represent important structure ele- different chemical structure bind at the same site as benzo- ments that confer binding or signal transduction specificity. diazepines and with similar affinity, although they elicit We chose this approach to determine which amino acids different behavioral effects. These compounds include tria- are involved in the differential binding of CL 218872. By zolopyridazines, imidazopyridines, cyclopyrrolones, pyra- assaying the displacement of [3H]Ro 15-1788 (a nonselective zoloquinolinones, and /3-carbolines (3). GABA is the major benzodiazepine antagonist) binding and by mutating the inhibitory neurotransmitter in the brain, and its receptors are low-affinity form to the high-affinity form, we hoped to present on a majority of neurons, which perhaps explains the eliminate changes of a nonspecific nature. We found that a wide range of effects of benzodiazepines and other com- single amino acid change, from a glutamate to a glycine at pounds acting at that site. The GABAA receptor contains an position 225 in the a3 amino acid sequence, substantially intrinsic chloride channel whose gated activity most often increased the affinity of the a3 subunit-containing receptor hyperpolarizes the cell and inhibits excitation. Benzodiaz- for CL 218872. A slightly larger shift resulted from changing epines, in the presence of GABA, increase GABAA receptor an additional three adjacent residues. The altered binding was chloride channel activity and inhibitory tone throughout the observed for several other selective compounds tested. central nervous system (4). Molecular cloning has led to the characterization of nu- merous sequence-related subunits of the GABAA receptor, MATERIALS AND METHODS including six a subunits (5-9), three f8 subunits (10), two y Construction of Chimeric Receptors. Conserved Nco I subunits (11, 12), and a 8 subunit (13). Recombinant coex- restriction sites occur in homologous positions in the rat a, pression of these subunits has produced receptor channels and a3 subunit cDNAs. By cleavage at these sites, a fragment that differ in their pharmacological (6, 8, 14, 15) and biophys- was removed from the a1 cDNA and then used to replace the ical (16-18) properties, suggesting that the heterogeneity of homologous fragment in the rat a3 cDNA (chimera 3). Partial natural GABAA receptors exceeds previous estimates based digests with Nco I allowed the exchange of larger fragments on ligand binding studies in brain membranes. Although the encoding N- or C-terminal domains (chimeras 1 and 2) into true extent of this heterogeneity is unknown, it is important the appropriate positions. All these constructs were made in to note that ternary receptors reconstituted from a, /3, and y the pBluescript phagemid (Stratagene), which lacks Nco I subunits have binding sites for benzodiazepines and channel sites. The chimeric cDNAs were then subcloned into the activities that can be modulated by these compounds (11, 12). pCDM8 expression vector (25). If such ternary receptors contain a y2 subunit, the a subunit Oligonucleotide-Mediated Mutagenesis. Site-directed muta- variant primarily determines the affinity profile of the ben- genesis was performed as described (26) by using the oligo- zodiazepine site (6, 8, 15). Thus, the a6 subunit defines a nucleotides 5'-GCGTGAGCCATCCTCAGCTACTTC- receptor that binds Ro 15-4513 but not diazepam or other CAC-3' (Ml); 5'-TCCTGTACTAGACTGGACTATCCCT- The publication costs of this article were defrayed in part by page charge Abbreviations: GABA, y-aminobutyric acid; GABAA receptor, type payment. This article must therefore be hereby marked "advertisement" A GABA receptor. in accordance with 18 U.S.C. §1734 solely to indicate this fact. fTo whom reprint requests should be addressed. 1421 Downloaded by guest on September 30, 2021 1422 Neurobiology: Pritchett and Seeburg Proc. Natl. Acad. Sci. USA 88 (1991) GTGTCAACAACATGACCAAG-3' (M2); 5'-AGATTT- constructed by exchanging homologous DNA restriction GTTCTTCTCACGAGTCCAITCATAAATTACTTCAGC- fragments between these cDNAs (Fig. 1). Expression con- TCTGGTATAGGCATA-3' (M3); 5'-TGTACTAGACTG- structs carrying the chimeric sequences were used along with GATTATC-3' (M20); 5'-ACTAGACCGGACTATCTCT-3' expression constructs encoding the rat Y2 and the rat 132 (M21); 5'-GGATTATCCCTGTCCCAAC-3' (M22); 5'- subunits for transient transfection of subconfluent 293 cells. TATCTCTGTGTCAACAACATG-3' (M23), and, as a tem- Membranes from these cells were incubated with [3H]Ro plate, single-stranded phagemid DNA containing the rat a3 15-1788 at a concentration equivalent to its Kd (1 nM), and subunit cDNA sequence. Bacterial colonies transformed the displacement of that binding was examined by including with mutagenized DNA were screened by hybridization with results of the oligonucleotides used for mutagenesis. Plasmid DNA various concentrations ofthe displacing ligand. The isolated from hybridizing colonies was sequenced, and the experiments using CL 218872 to displace [3H]Ro 15-1788 correct DNA was used for construction ofeukaryotic expres- (Fig. 1) indicated that the extracellular portion of the a sion plasmids. subunit was responsible for the distinctive pharmacological DNA Transfection in Cultured Cells. Cloned cDNAs en- profile of the particular receptor subtype, although the si- coding the rat ax, 82, and Y2 subunits were subcloned into the multaneous expression of all a, 13, and 'y subunits was pCDM8 expression vector (Invitrogen, San Diego, CA) by necessary for binding of benzodiazepines. standard procedures. Various amounts of5' (100-500 bp) and The comparison of the amino acid sequences of the a,, a2, 3' (100-2000 bp) untranslated regions were included for and a3 subunits from species expressing high- and low- convenience in the subcloning and did not noticeably affect affinity CL 218872 binding sites (rat, bovine, and human) the results. DNAs were combined in equal amounts and reveals clusters of amino acid substitutions in the extracel- added in transfection buffer (27) to exponentially growing lular domain of the a subunit variants (ref. 5; P.H.S., human embryonic kidney 293 cells (ATCC CRL 1573) (14). unpublished data). Particular positions in which the a, sub- After an overnight incubation, medium was removed, and the unit sequences differ from both the a2 and a3 subunit se- cells were washed once with serum-free medium, and then quences were considered likely candidates for residues af- refed serum-containing medium. fecting binding affinities ofselective benzodiazepine receptor Membrane Preparation and Binding Experiments. Cells compounds. Three such clusters were targeted for mutagen- were harvested from plates 48 hr after transfection by re- esis. Oligonucleotides were constructed
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