How Structurally Diverse General Anesthetics Work on GABA Type A Receptors♦

♦ See referenced article, J. Biol. Chem. 2013, 288, 19343–19357

GABA type A receptors (GABA_ARs), the major inhibitory neurotransmitter receptors in the brain, are the primary targets of many general anesthetics. Researchers have wanted to know how structurally different anesthetics can all modulate GABA_ARs and have similar effects. In this Paper of the Week, a team led by Jonathan B. Cohen at Harvard Medical School and Keith W. Miller at Massachusetts General Hospital used photoreactive analogs of the general anesthetics etomidate and phenobarbital to map out where these different compounds bind in GABA_ARs. They established that a photoreactive barbiturate bound to a human GABA_AR subtype within the transmembrane domain at the α⁺-β⁻ and γ⁺-β⁻ interfaces. These interfaces were distinct from, but homologous to, sites bound by the etomidate analogs (β⁺-α⁻). They further showed that propofol and some barbiturates bound nonselectively to all four anesthetic sites. “The structural heterogeneity of barbiturate, etomidate, and propofol derivatives is accommodated by varying selectivities for these two classes of sites,” say the authors. “We hypothesize that binding at any of these homologous intersubunit sites is sufficient for anesthetic action and that this explains to some degree the puzzling structural heterogeneity of anesthetics.”

Intersubunit drug-binding sites in a GABA_AR. Left, in the extracellular domain, there are binding sites for the neurotransmitter GABA (green) and for benzodiazepines (blue). Right, in the transmembrane domain, there are distinct binding sites for the general anesthetic etomidate (brown) and a high affinity barbiturate (red).