Volatile Anesthesia and the GABAA Receptor Gamma Subunit

描述（由申请人提供）：挥发性麻醉剂是一种广泛使用的药物，可产生显著的毒性作用，但其分子靶点和作用机制尚不明确。我们研究的总体目标是确定神经系统中吸入麻醉剂起作用的关键分子位点。这一信息是需要的，以便设计出具有更大特异性的药物，以达到理想的作用和更少的毒副作用。γ -氨基丁酸A型（GABAA）受体可能是一个重要的麻醉靶点。哺乳动物大脑中大多数GABAA受体由α、β和γ亚基组成。分子研究主要是利用缺乏伽马亚基的表达GABAA受体获得的，已经确定了对挥发性麻醉剂调节至关重要的位点。然而，我们发现，与不含伽马亚基的受体相比，将伽马亚基掺入表达的GABAA受体会降低对挥发性麻醉剂的敏感性。并且基本上消除了在假定的挥发性麻醉位点突变对α亚基（α S2701）的影响。我们的工作假设是，γ亚基包含特定的结构特征，可以调节挥发性麻醉对GABAA受体的作用。我们建议：1)确定在存在和不存在挥发性麻醉剂的情况下γ亚基对GABAA受体功能的影响；2)定位γ亚基中对挥发性麻醉剂作用调节至关重要的部分；3)确定该亚基如何改变假定的α亚基麻醉部位突变的影响。

DESCRIPTION (provided by applicant): 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.