Consistent with their roles in mediating neuronal inhibition, deficits in GABAB receptor function play significant roles in both neurological and psychiatric disorders that include ischemia, epilepsy, schizophrenia, addiction, and nociception. Given the clear significance of GABAB receptors in neurotransmission it is of fundamental importance to understand the endogenous mechanisms neurons use to regulate their activity under both control and pathological conditions. Previous studies from our laboratory have illustrated that GABAB receptors are phosphorylated by intimately-associated AMP-dependent protein kinase (AMPK) a process that enhances their activity, together with the strength of neuronal inhibition. AMPK is a key enzyme in regulating cellular levels of ATP and in mediating cellular responses to metabolic stressors that include ischemia and anoxia. Transient anoxia also increases AMPK-phosphorylation of GABAB receptors and neuronal survival after this trauma. In concordance with our results it is well documented that the GABAB agonist baclofen is neuroprotective in animal models of ischemia and is used """"""""off-label"""""""" to aid recovery of patients after stroke. Given the established role of glutamate receptors in ischemia-induced excitotoxicity we have begun to explore the link between their activation and the regulation of AMPK-dependent phosphorylation of GABAB receptors. These preliminary studies have led us to formulate our central hypothesis: Prolonged exposure of neurons to glutamate via the activation of NMDA receptors inhibits AMPK-dependent phosphorylation of GABAB receptors. This deficit in phosphorylation enhances GABAB receptor ubiquitination, promoting their endocytosis from the plasma membrane and thereby reducing the efficacy of neuronal inhibition mediated by these critical GPCRS. Our experiments will focus on four distinct but related specific aims. 1. We will test the hypothesis that glutamate receptors modulate GABAB receptor phosphorylation and functional coupling. 2. We will test the hypothesis that glutamate receptor activation modulates the endocytosis and endocytic sorting of GABAB receptors. 3. We will test the hypothesis that inhibiting PP2A and proteasome activity regulates the effects of glutamate receptor activation on GABAB receptor cell surface stability. 4. We will test the hypothesis that blocking GABAB receptor dephosphorylation promotes neuronal survival after anoxia.
GABAB receptors are G-protein coupled receptors (GPCRs) that mediate slow and prolonged synaptic inhibition in the brain. Results of the experiments in this proposal will provide insights into the biochemical regulation of neuronal GABAB receptors under control and after anoxic insult similar to that occurring following ischemic brain injury. Given the critical roles that GABAB receptors play in regulating neuronal inhibition our studies will have the potential to make contributions to the development of novel therapeutics to enhance neuronal survival after ischemic injury and to alleviate other debilitating disorders including epilepsy, depression, schizophrenia, and pain.
|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|
Showing the most recent 10 out of 50 publications