GABAergic transmission is an integral part of retinal signal processing, and has been implicated in such functions as directional sensitivity, center-surround receptive field, and color opponency. Dysfunction of GABA neurotransmission has also been implicated in a broad range of neural disorders. Three types of GABA receptors (GABA-A, GABA-B and GABA-C) have been identified. The GABA-C receptors are present prominently in the retina, and exhibit unique properties that are well suited for retinal signal processing. The genes of GABA-C receptor subunits have been located in a locus where several hereditary retinal diseases are linked. The long-term goals of the proposed research are to understand the molecular structure and physiological function of the GABA-C receptors present on diverse retinal neurons. In this proposal, combined electrophysiological, molecular biological and biochemical approaches will be used to study the subunit composition, receptor clustering and biophysical properties of the GABA-C receptors. In particular, we hypothesize that the native GABA-C receptors are formed by co-assembly of gamma2 with multiple rho subunits. The assembly mechanism of these heterooligomeric receptors will be investigated, and the participation of gamma2 subunit in forming the native GABA-C receptors will be examined by antisense oligonucleotide techniques and by immunoprecipitation experiments. In addition, receptor clustering and anchoring are essential for normal signal transmission in neurons. The intracellular proteins interacting with GABA-C receptors will be identified by yeast two-hybrid screening techniques, and their function in modulating GABA-C receptor activities will be examined. Furthermore, the pharmacological and biophysical properties of the GABA-C receptors will be determined both in expression systems and in retinal neurons. These experiments will provide insights into the subunit composition and diversity of native GABA-C receptors. Our studies will help to reveal how GABA-C receptors on retinal neurons are assembled and placed on the plasma membrane, and how the activities of these receptors are dynamically regulated. The information gained from these studies will enhance our knowledge about the physiological function of the GABA-C receptor in the retina, and broaden our understanding of retinal signal processing mechanisms.
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