Gamma-aminobutyric acid (GABA) is the main inhibitory neurotransmitter in the mammalian brain. GABA exerts its physiological actions in the brain via the activation of two distinct types of receptor: GABA-A receptors, which are ligand-gated ion channels, and GABA-B receptors, which are G proteincoupled receptors. GABA-A and GABA-B receptors are known to exhibit forms of cross-talk and mutual regulation for which no mechanism has been defined. This project aims to study the importance of a novel and direct interaction found between the GABA-BR1 receptor and the gamma2 subunit of the GABA-A receptor. This physical association may provide a mechanism to allow for direct cross-talk between GABA-A and GABA-B receptors. The structural determinants and physiological significance of this interaction, however, are completely unknown at the present time. The specific regions of GABA-BR1 and the gamma2 subunit of the GABA-A receptor involved in mediating their interaction will be elucidated using a mutagenesis approach in combination with both co-immunoprecipitation and fusion protein pull-down studies. The effects of GABA-A receptor association on GABA-B receptor pharmacology will be studied in ligand binding assays, and GABA-A receptor modulation of GABA-B receptor signaling and internalization will also be analyzed. Furthermore, GABA-B receptor regulation of GABA-A receptor pharmacology, channel activity and phosphorylation will be examined, with an emphasis on determining the functional importance of the direct interaction between GABA-BR1 and the GABA-A receptor gamma2 subunit. These studies will shed new light on the regulation of cellular responses to GABA and the molecular basis for cross-talk between GABA-A and GABA-B receptors. Such information is critical for a comprehensive understanding of pharmaceuticals acting on GABA receptors. GABA-A receptors are the targets for such commonly prescribed therapeutic drugs as benzodiazepines and barbiturates, while the more recently-identified GABA-B receptors represent excellent potential targets for novel therapeutic drugs aimed at treating disorders such as schizophrenia, epilepsy, anxiety, chronic pain and depression.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Molecular, Cellular and Developmental Neurosciences 2 (MDCN)
Program Officer
Stewart, Randall
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Emory University
Schools of Medicine
United States
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Balasubramanian, Srividya; Fam, Sami R; Hall, Randy A (2007) GABAB receptor association with the PDZ scaffold Mupp1 alters receptor stability and function. J Biol Chem 282:4162-71
Yun, C Chris; Sun, Hong; Wang, Dongsheng et al. (2005) LPA2 receptor mediates mitogenic signals in human colon cancer cells. Am J Physiol Cell Physiol 289:C2-11
Kuwajima, Masaaki; Hall, Randy A; Aiba, Atsu et al. (2004) Subcellular and subsynaptic localization of group I metabotropic glutamate receptors in the monkey subthalamic nucleus. J Comp Neurol 474:589-602
Charara, Ali; Galvan, Adriana; Kuwajima, Masaaki et al. (2004) An electron microscope immunocytochemical study of GABA(B) R2 receptors in the monkey basal ganglia: a comparative analysis with GABA(B) R1 receptor distribution. J Comp Neurol 476:65-79
Balasubramanian, Srividya; Teissere, Jeremy A; Raju, Dinesh V et al. (2004) Hetero-oligomerization between GABAA and GABAB receptors regulates GABAB receptor trafficking. J Biol Chem 279:18840-50
Hall, Randy A (2004) Beta-adrenergic receptors and their interacting proteins. Semin Cell Dev Biol 15:281-8