Department of Physiology and Biophysics, State University of New York at Buffalo, Buffalo, New York.
Department of Physiology and Biophysics, State University of New York at Buffalo, Buffalo, New York.
Biophys J. 2021 May 4;120(9):1800-1813. doi: 10.1016/j.bpj.2021.02.034. Epub 2021 Mar 4.
Agonists are evaluated by a concentration-response curve (CRC), with a midpoint (EC) that indicates potency, a high-concentration asymptote that indicates efficacy, and a low-concentration asymptote that indicates constitutive activity. A third agonist attribute, efficiency (η), is the fraction of binding energy that is applied to the conformational change that activates the receptor. We show that η can be calculated from EC and the asymptotes of a CRC derived from either single-channel or whole-cell responses. For 20 agonists of skeletal muscle nicotinic receptors, the distribution of η-values is bimodal with population means at 51% (including acetylcholine, nornicotine, and dimethylphenylpiperazinium) and 40% (including epibatidine, varenicline, and cytisine). The value of η is related inversely to the size of the agonist's headgroup, with high- versus low-efficiency ligands having an average volume of 70 vs. 102 Å. Most binding site mutations have only a small effect on acetylcholine efficiency, except for αY190A (35%), αW149A (60%), and those at αG153 (42%). If η is known, the EC and high-concentration asymptote can be calculated from each other. Hence, an entire CRC can be estimated from the response to a single agonist concentration, and efficacy can be estimated from EC of a CRC that has been normalized to 1. Given η, the level of constitutive activity can be estimated from a single CRC.
激动剂通过浓度-反应曲线（CRC）进行评估，其中中点（EC）表示效力，高浓度渐近线表示效能，低浓度渐近线表示组成活性。激动剂的第三个属性是效率（η），它是将结合能的一部分应用于激活受体的构象变化的分数。我们表明，η可以从 EC 和源自单通道或全细胞反应的 CRC 的渐近线计算得出。对于 20 种骨骼肌烟碱受体激动剂，η 值的分布呈双峰分布，群体平均值分别为 51%（包括乙酰胆碱、去甲烟碱和二甲苯基哌嗪）和 40%（包括依匹卡丁、伐仑克林和烟碱）。η 值与激动剂头部基团的大小成反比，高效和低效配体的平均体积分别为 70 和 102 Å。除了 αY190A（35%）、αW149A（60%）和 αG153 处的突变（42%）外，大多数结合位点突变对乙酰胆碱的效率只有很小的影响。如果知道 η，EC 和高浓度渐近线可以相互计算。因此，可以从单个激动剂浓度的响应来估计整个 CRC，并且可以从已归一化为 1 的 CRC 的 EC 来估计效能。给定 η，可以从单个 CRC 估计组成活性的水平。
