Review
doi: 10.1007/s00213-009-1562-z. Epub 2009 May 20.The role of GABA(A) receptors in the acute and chronic effects of ethanol: a decade of progress
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- PMCID: PMC2814770
- DOI: 10.1007/s00213-009-1562-z
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Review
The role of GABA(A) receptors in the acute and chronic effects of ethanol: a decade of progress
Sandeep Kumar et al. Psychopharmacology (Berl).2009 Sep.
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Abstract
The past decade has brought many advances in our understanding of GABA(A) receptor-mediated ethanol action in the central nervous system. We now know that specific GABA(A) receptor subtypes are sensitive to ethanol at doses attained during social drinking while other subtypes respond to ethanol at doses attained by severe intoxication. Furthermore, ethanol increases GABAergic neurotransmission through indirect effects, including the elevation of endogenous GABAergic neuroactive steroids, presynaptic release of GABA, and dephosphorylation of GABA(A) receptors promoting increases in GABA sensitivity. Ethanol's effects on intracellular signaling also influence GABAergic transmission in multiple ways that vary across brain regions and cell types. The effects of chronic ethanol administration are influenced by adaptations in GABA(A) receptor function, expression, trafficking, and subcellular localization that contribute to ethanol tolerance, dependence, and withdrawal hyperexcitability. Adolescents exhibit altered sensitivity to ethanol actions, the tendency for higher drinking and longer lasting GABAergic adaptations to chronic ethanol administration. The elucidation of the mechanisms that underlie adaptations to ethanol exposure are leading to a better understanding of the regulation of inhibitory transmission and new targets for therapies to support recovery from ethanol withdrawal and alcoholism.
Figures
Mechanisms of GABAA receptor endocytosis and recycling. Endocytosis by clathrin-coated vesicles requires adaptor complex-2 (AP-2) and clathrin binding to the receptor. AP-2 is specific for endocytosis of surface proteins including GABAA receptors. First, AP-2 recognizes and binds to GABAA receptors, then clathrin binds the complex and the receptor is internalized. Phosphorylation of GABAA receptors can prevent AP-2 binding and subsequent internalization. Internalized receptors may be recycled back to the cell surface or degraded depending upon undefined intracellular signals. Protein kinases can alter many steps in the receptor trafficking process. For example, PKC phosphorylation can alter recycling of receptors, whereas PKA can increase surface expression of GABAA receptors. Adaptor complex-1 (AP-1) transports newly synthesized receptors from the trans-Golgi reticulum to the cell surface. Many proteins are required for intracellular trafficking of GABAA receptors. For example, GABAA receptor-associated protein (GABARAP) is involved in trafficking of GABAA receptors from the endoplasmic reticulum/Golgi complex towards the plasma membrane and possibly also in vesicle-mediated cycling between the plasma membrane and cytoplasmic pool of receptors.N-ethylmaleimide-sensitive factor (NSF) interacts with GABARAP and influences intracellular trafficking of GABAA receptors. Gephyrin reduces the diffusion of GABAA receptors from the membrane and facilitates their clustering at synapses. Protein linking integrin-associated protein to cytoskeleton-1 (Plic-1) is also involved in GABAA receptor trafficking and facilitates surface expression of the receptors (see Chen and Olsen 2007 for review)
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