Mapping the contribution of β3-containing GABAA receptors to volatile and intravenous general anesthetic actions

Abstract

Background: Agents belonging to diverse chemical classes are used clinically as general anesthetics. The molecular targets mediating their actions are however still only poorly defined. Both chemical diversity and substantial differences in the clinical actions of general anesthetics suggest that general anesthetic agents may have distinct pharmacological targets. It was demonstrated previously that the immobilizing action of etomidate and propofol is completely, and the immobilizing action of isoflurane partly mediated, by β3-containing GABA A receptors. This was determined by using the β3(N265M) mice, which carry a point mutation known to decrease the actions of general anesthetics at recombinant GABA A receptors. In this communication, we analyzed the contribution of β3-containing GABA A receptors to the pharmacological actions of isoflurane, etomidate and propofol by means of β3(N265M) mice.

γ-Aminobutyric Acid (GABA) and Pentobarbital Induce Different Conformational Rearrangements in the GABAA Receptor α1 and β2 Pre-M1 Regions

“…Propofol blocks covalent modification of ␤M286C by sulfhydryl-specific reagents, indicating that this residue forms part of a general anesthetic binding site (29). Furthermore, a knock-in mouse for ␤N265M removes the immobilizing and hypnotic actions of PB as well as the actions of etomidate and propofol (30). Taken together, the data indicate that general anesthetics, including PB, likely share a similar binding site, which is located in a water-filled pocket ϳ50 Å below the GABA binding site between M1, M2, and M3.…”

Etomidate blocks LTP and impairs learning but does not enhance tonic inhibition in mice carrying the N265M point mutation in the beta3 subunit of the GABAA receptor

“…Previous experiments in β3-N265M mice similarly showed that propofol-induced amnesia is independent of β3-GABA A Rs (Zeller et al, 2007). Experiments with isoflurane produced conflicting results: studies in β3-N265M knock-in mice indicated no contribution of β3 subunits (Liao et al, 2005) but studies in forebrain-specific knockout suggested a partial contribution (Rau et al, 2011).…”

A community-based cluster randomized survey of noncommunicable disease and risk factors in a peri-urban shantytown in Lima, Peru

“…Primary intermediary factors that are expected to be prevalent in a slum setting and contribute to the development of noncommunicable disease include inadequate access to sanitation and other infrastructure [5], insecure residential status [5], and exposure to violence and crime. In informal settlements, chronic noncommunicable diseases are at particular risk of going undetected by formal health registries until presentation in a late stage of disease or death; this has been attributed to a lack of access to health services and inadequate or inappropriate care when services are sought [4,5]. This pattern of health-seeking behavior typically results in an undue human cost and financial burden on existing health systems [3,4], underscoring the need for noncommunicable disease (NCD) data to advise health interventions targeting the urban poor.…”

“…In informal settlements, chronic noncommunicable diseases are at particular risk of going undetected by formal health registries until presentation in a late stage of disease or death; this has been attributed to a lack of access to health services and inadequate or inappropriate care when services are sought [4,5]. This pattern of health-seeking behavior typically results in an undue human cost and financial burden on existing health systems [3,4], underscoring the need for noncommunicable disease (NCD) data to advise health interventions targeting the urban poor.…”