Regulation of GABAA receptors by prolonged exposure to endogenous and exogenous ligands

GRAVIELLE, M. C.

NEUROCHEMISTRY INTERNATIONAL

PERGAMON-ELSEVIER SCIENCE LTD

Lugar: Amsterdam; Año: 2018 vol. 118 p. 96 - 104

0197-0186

GABAA receptors mediate most of the fastinhibitory transmissions in the central nervous system. These receptors arepentameric complexes that exhibit high structural and pharmacologicalheterogeneity, as they can be constructed from 19 distinct subunits. GABAAreceptors are the targets of numerous clinically relevant drugs used to treat variousdisorders such as anxiety, insomnia and epilepsy. These receptors are also the targetsof many volatile anesthetics and drugs of abuse, such as alcohol. This reviewis focused on the effect of long-term treatment with GABA, and the positiveallosteric modulators benzodiazepines, neurosteroids and ethanol on GABAAreceptors. Prolonged exposure of GABAA receptors to these compounds triggersseveral adaptive mechanisms that lead to changes in the structure, function andlocalization of receptors. These changes include GABAA receptorsubunit expression, intracellular trafficking and phosphorylation. Theseadaptations are relevant to different physiological, pathological and pharmacologicalconditions and, in most cases, are associated with the development oftolerance. Understanding the molecular mechanisms underlying these regulatoryprocesses will be relevant for therapeutic benefits.