Volatile anesthetics are widely utilized drugs that can produce significant toxic effects, yet their molecular targets and mechanisms of action are poorly defined The overall aim of our research is to identify critical molecular sites in the nervous system where inhaled anesthetics act. This information is needed in order to design drugs with greater specificity for desirable actions and fewer toxic side-effects. The gamma-aminobutyric acid type A (GABAA) receptor is likely an important anesthetic target. Most GABAA receptors in mammalian brain are composed of alpha, beta, and gamma subunits. Molecular studies, largely obtained using expressed GABAA receptors lacking gamma subunits, have identified sites that appear critical for modulation by volatile anesthetics However, we have found that incorporation of gamma subunits into expressed GABAA receptors both reduces sensitivity to volatile anesthetics compared with gamma-less receptors, and essentially nullifies the impact of a mutation at the putative volatile anesthetic site on the alpha subunit (alpha S2701) Our working hypothesis is that the gamma subunit contains specific structural features that modulate volatile anesthetic actions on GABAA receptors. We propose to 1) ascertain the impact of the gamma subunit on GABAA receptor function in the presence and absence of volatile anesthetics, 2) locate portions of the gamma subunit that are critical for modulation of volatile anesthetic actions, and 3) determine how the subunit alters the effects of mutations at the putative alpha subunit anesthetic site.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM066724-06
Application #
7369776
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Program Officer
Cole, Alison E
Project Start
2003-03-01
Project End
2009-08-31
Budget Start
2008-03-01
Budget End
2009-02-28
Support Year
6
Fiscal Year
2008
Total Cost
$287,332
Indirect Cost
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02199
Forman, Stuart A (2011) Clinical and molecular pharmacology of etomidate. Anesthesiology 114:695-707
Forman, Stuart A; Miller, Keith W (2011) Anesthetic sites and allosteric mechanisms of action on Cys-loop ligand-gated ion channels. Can J Anaesth 58:191-205
Forman, Stuart A (2010) Molecular approaches to improving general anesthetics. Anesthesiol Clin 28:761-71
Vanderweyde, Tara; Bednar, Martin M; Forman, Stuart A et al. (2010) Iatrogenic risk factors for Alzheimer's disease: surgery and anesthesia. J Alzheimers Dis 22 Suppl 3:91-104
Desai, Rooma; Ruesch, Dirk; Forman, Stuart A (2009) Gamma-amino butyric acid type A receptor mutations at beta2N265 alter etomidate efficacy while preserving basal and agonist-dependent activity. Anesthesiology 111:774-84
Stewart, Deirdre; Desai, Rooma; Cheng, Qi et al. (2008) Tryptophan mutations at azi-etomidate photo-incorporation sites on alpha1 or beta2 subunits enhance GABAA receptor gating and reduce etomidate modulation. Mol Pharmacol 74:1687-95
Zhong, Huijun; Rusch, Dirk; Forman, Stuart A (2008) Photo-activated azi-etomidate, a general anesthetic photolabel, irreversibly enhances gating and desensitization of gamma-aminobutyric acid type A receptors. Anesthesiology 108:103-12
Forman, Stuart A; Chin, Victor A (2008) General anesthetics and molecular mechanisms of unconsciousness. Int Anesthesiol Clin 46:43-53
Forman, Stuart A; Zhou, Qiong L; Stewart, Deirdre S (2007) Photoactivated 3-azioctanol irreversibly desensitizes muscle nicotinic ACh receptors via interactions at alphaE262. Biochemistry 46:11911-8
Rusch, Dirk; Forman, Stuart A (2005) Classic benzodiazepines modulate the open-close equilibrium in alpha1beta2gamma2L gamma-aminobutyric acid type A receptors. Anesthesiology 102:783-92

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