GABAB receptors are the major sites of slow synaptic inhibition in the brain. Changes in GABAB receptor function play key roles in epilepsy, nociception, depression, addiction, mental retardation and neuroprotection. The number of GABAB receptors expressed on the cell surface of neurons is dependent on the formation of heterodimers between GABABR1 and R2 subunits. Recent studies have demonstrated that once at the cell surface GABAB receptors are stable entities, which do not undergo agonist-induced internalization. Therefore primary determinants of the efficacy of slow synaptic inhibition mediated by GABAB receptors will be the production of receptor heterodimers, the trafficking of assembled heterodimers to the cell surface, and their coupling to the appropriate effectors. Here we hypothesize that GABAB receptor activity is regulated by the activity of AMP-dependent protein kinase (AMPK), which phosphorylates serine residues within both receptor subunits. Phosphorylation increases GABAB receptor cell surface expression levels by enhancing receptor trafficking and assembly in the secretory pathway. In addition, phosphorylation by AMPK enhances receptor-effector coupling by reducing desensitization. Therefore AMPK activity provides a dynamic mechanism for regulating the efficacy of GABAB receptor signaling. We will use a combination of cell biological, biochemical and electrophysiological approaches to carry out three independent but related specific aims: 1. To test the hypothesis that GABAB receptor are dynamically phosphorylated by intimately associated AMPK. 2. To test the hypothesis that direct phosphorylation of GABAB receptor by AMPK regulates receptor cell surface stability and effector coupling. 3. To test the hypothesis that AMPK activity modifies GABAB receptor membrane trafficking and assembly. Together, our approaches will provide a more thorough understanding of the cell surface stability and function of GABAB receptors. The results of these studies will have the potential to make significant contributions to the development of novel therapeutic strategies for such debilitating disorders as epilepsy, nociception, depression, addiction, and mental retardation.
| Rifkin, Robert A; Moss, Stephen J; Slesinger, Paul A (2017) G Protein-Gated Potassium Channels: A Link to Drug Addiction. Trends Pharmacol Sci 38:378-392 |
| Trattnig, Sarah M; Gasiorek, Agnes; Deeb, Tarek Z et al. (2016) Copper and protons directly activate the zinc-activated channel. Biochem Pharmacol 103:109-17 |
| Mircsof, Dennis; Langouët, Maéva; Rio, Marlène et al. (2015) Mutations in NONO lead to syndromic intellectual disability and inhibitory synaptic defects. Nat Neurosci 18:1731-6 |
| Terunuma, Miho; Haydon, Philip G; Pangalos, Menelas N et al. (2015) Purinergic receptor activation facilitates astrocytic GABAB receptor calcium signalling. Neuropharmacology 88:74-81 |
| Abramian, Armen M; Comenencia-Ortiz, Eydith; Modgil, Amit et al. (2014) Neurosteroids promote phosphorylation and membrane insertion of extrasynaptic GABAA receptors. Proc Natl Acad Sci U S A 111:7132-7 |
| Kahle, Kristopher T; Deeb, Tarek Z; Puskarjov, Martin et al. (2013) Modulation of neuronal activity by phosphorylation of the K-Cl cotransporter KCC2. Trends Neurosci 36:726-737 |
| Deeb, Tarek Z; Nakamura, Yasuko; Frost, Greg D et al. (2013) Disrupted Cl(-) homeostasis contributes to reductions in the inhibitory efficacy of diazepam during hyperexcited states. Eur J Neurosci 38:2453-67 |
| Gonzalez, Claudia; Moss, Stephen J; Olsen, Richard W (2012) Ethanol promotes clathrin adaptor-mediated endocytosis via the intracellular domain of ?-containing GABAA receptors. J Neurosci 32:17874-81 |
| Deeb, Tarek Z; Maguire, Jamie; Moss, Stephen J (2012) Possible alterations in GABAA receptor signaling that underlie benzodiazepine-resistant seizures. Epilepsia 53 Suppl 9:79-88 |
| Wang, Dian-Shi; Zurek, Agnieszka A; Lecker, Irene et al. (2012) Memory deficits induced by inflammation are regulated by ?5-subunit-containing GABAA receptors. Cell Rep 2:488-96 |
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