Regulating the Efficacy of Inhibition Through Trafficking of γ-Aminobutyric Acid Type A Receptors

Trafficking of anesthetic-sensitive receptors within the plasma membrane, or from one cellular component to another, occurs continuously. Changes in receptor trafficking have implications in altering anesthetic sensitivity. γ-Aminobutyric acid type A receptors (GABA A Rs) are anion-permeable ion channels and are the major class of receptor in the adult mammalian central nervous system that mediates inhibition. GABAergic signaling allows for precise synchronized firing of action potentials within brain circuits that is critical for cognition, behavior, and consciousness. This precision depends upon tightly controlled trafficking of GABA A Rs into the membrane. General anesthetics bind to and allosterically enhance GABA A Rs by prolonging the open state of the receptor and thereby altering neuronal and brain circuit activity. Subunit composition and GABA A R localization strongly influence anesthetic end points; therefore, changes in GABA A R trafficking could have significant consequences to anesthetic sensitivity. GABA A Rs are not static membrane structures but are in a constant state of flux between extrasynaptic and synaptic locations and are continually endocytosed and recycled from and to the membrane. Neuronal activity, posttranslational modifications, and some naturally occurring and synthetic compounds can influence the expression and trafficking of GABA A Rs. In this article, we review GABA A Rs, their trafficking, and how phosphorylation of GABA A R subunits can influence the surface expression and function of the receptor. Ultimately, alterations of GABA A R trafficking could modify anesthetic end points, both unintentionally through pathologic processes but potentially as a therapeutic target to adjust anesthetic-sensitive GABA A Rs.