Regulation of excitation by GABAA a receptor internalization

Abstract

Neuronal inhibition is of paramount importance in maintaining the delicate and dynamic balance between excitatory and inhibitory influences in the central nervous system. GABA (γ-aminobutyric acid), the primary inhibitory neurotransmitter in brain, exerts its fast inhibitory effects through ubiquitously expressed GABAA receptors. Activation of these heteropentameric receptors by GABA results in the gating of an integral chloride channel leading to membrane hyperpolarization and neuronal inhibition. To participate in neurotransmission, the receptor must reside on the cell surface. The trafficking of nascent receptors to the cell surface involves posttranslational modification and the interaction of the receptor with proteins that reside within the secretory pathway. The subsequent insertion of the receptor into specialized regions of the plasma membrane is dictated by receptor composition and other factors that guide insertion at synaptic or perisynaptic/extrasynaptic sites, where phasic and tonic inhibition are mediated, respectively. Once at the cell surface, the receptor is laterally mobile and subject to both constitutive and regulated endocytosis. Following endocytosis the receptor undergoes either recycling to the plasma membrane or degradation. These dynamic processes profoundly affect the strength of GABAergic signaling, neuronal inhibition, and presumably synaptic plasticity. Heritable channelopathies that affect receptor trafficking have been recently recognized and compelling evidence exists that mechanisms underlying acquired epilepsy involve GABAA receptor internalization. Additionally, GABAA receptor endocytosis has been identified as an early event in the ischemic response that leads to excitotoxicity and cell death. This chapter summarizes what is known regarding the regulation of receptor trafficking and cell surface expression and its impact on nervous system function from both cell biology and disease perspectives. © 2007 Springer-Verlag Berlin Heidelberg.