Synaptic transmission at chemical synapses in the CNS involves a relatively well-described sequences of events in which neurotransmitter is released from the presynaptic terminal and interacts with postsynaptic receptors that transduce ligand binding into a postsynaptic response. A major questions in neurobiology is how postsynaptic receptors are regulated to changing conditions. The GABAA/benzodiazepine receptor (GABA/BZD-R) is of particular interest in this respect, since the response to its transmitter, GABA, is allosterically modulated by benzodiazepines (BZDs) which act at a separate site on the GABA/BAD-R. Remarkably, the modulatory interaction of BZDs with th GABA/BZD-R is itself subject to regulation in response to chronic BZD exposure, and, moreover, the mode of regulation differs form that elicited by chronic exposure to GABAergic agonists. Whereas chronic exposure to GABAergic agonists results in down-regulation of GABA/BZD-R levels, chronic exposure to BZDs results in an """"""""uncoupling"""""""" of the allosteric interaction between the BZD recognition site and the GABA recognition site, with no change in receptor levels. Thus, the GABA/BZD-R exhibits two independent modes of homologous regulations: down-regulation induced by GABAergic agonists, and uncoupling induced by BZDs. Moveover, the GABA/BZD-R has now been found to exhibit heterologous regulation in response to chronic exposure to methylxanthines, such as caffeine and theophylline, which also produce uncoupling of GABA and BZD recognition sites, but which probably act through an adenosine receptor. The goal of this proposal is to investigate mechanism of homologous and heterologous GABA/BZD-R regulation in primary monolayer cell culture. Toward this end, the methods of radioligand binding, 36C1 uptake, and electrophysiology will be employed to determine the causes, mechanisms, and consequences of homologous and heterologous GABA/BZD-R regulation.
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