Volatile Anesthesia and the GABAA Receptor Gamma Subunit

描述（由申请人提供）：挥发性麻醉剂是广泛使用的药物，可产生显著的毒性作用，但其分子靶点和作用机制定义不清。我们研究的总体目标是确定吸入麻醉剂作用的神经系统中的关键分子位点。需要这些信息来设计具有更大特异性和更少毒副作用的药物。γ-氨基丁酸A型（GABAA）受体可能是重要的麻醉靶点。哺乳动物脑中的大多数GABAA受体由α、β和γ亚基组成。分子研究，主要是使用缺乏γ亚基的表达的GABAA受体获得的，已经鉴定了对于挥发性麻醉剂的调节似乎是关键的位点。然而，我们发现，与无γ受体相比，将γ亚基掺入表达的GABAA受体既降低了对挥发性麻醉剂的敏感性，并且基本上消除了假定的挥发性麻醉剂位点的突变对α亚基的影响（α S2701）我们的工作假设是γ亚基含有调节挥发性麻醉剂对GABAA受体作用的特定结构特征。我们建议：1）确定γ亚基对GABAA受体功能的影响，在存在和不存在挥发性麻醉剂的情况下，2）定位γ亚基的部分，这是挥发性麻醉剂的行动调制的关键，和3）确定亚基如何改变在假定的α亚基麻醉部位的突变的影响。

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.