Stickle D, Barber R
Laboratory of Cyclic Nucleotide Research, Graduate School of Biomedical Sciences, University of Texas Health Science Center, Houston 77225.
Mol Pharmacol. 1993 Mar;43(3):397-411.
The rate of adenylate cyclase activation via agonist-bound receptors in intact cells can be partly dependent on the rate of turnover of occupancy by agonist with respect to individual receptors. For instance, low occupancy of the full complement of receptors by epinephrine in intact S49 cells has been shown to promote a rate of activation that is substantially greater than that for high occupancy of a small number of receptors for which the concentration of epinephrine-bound receptors is the same. According to the encounter coupling model, a partial dependence of the relationship between receptor occupancy and adenylate cyclase activity on the agonist binding frequency can in principle be explained by episodic interactions of finite duration (encounters) between individual pairs of receptor and GTP-binding protein. The mean lifetime of the agonist-receptor complex and the frequency of binding relative to the mean duration of such encounters dictate whether there is variation of the state of the receptor during an encounter and the extent to which the overall rate of GTP-binding protein activation can be dependent on binding frequency. We present here a quantitative analysis of agonist concentration versus cyclase response curves in terms of the encounter coupling model that explicitly includes agonist binding frequency, the encounter frequency, and the encounter duration as parameters. The essential result is that the model is quantitatively consistent with concentration versus response curves for receptor-mediated activation of adenylate cyclase in S49 cells. It is also shown that the model is consistent with data on the differential effects of antagonists to inhibit agonist-stimulated cyclase activation in a manner that is dependent on the antagonist binding frequency.
在完整细胞中，通过与激动剂结合的受体激活腺苷酸环化酶的速率可能部分取决于激动剂相对于单个受体的占有率周转率。例如，在完整的S49细胞中，肾上腺素对全部受体的低占有率已被证明能促进激活速率，该速率显著高于少量受体高占有率时的激活速率，而此时肾上腺素结合受体的浓度是相同的。根据相遇偶联模型，受体占有率与腺苷酸环化酶活性之间的关系对激动剂结合频率的部分依赖性原则上可以通过单个受体与GTP结合蛋白对之间有限持续时间的偶发相互作用（相遇）来解释。激动剂-受体复合物的平均寿命以及相对于这种相遇平均持续时间的结合频率决定了相遇期间受体状态是否存在变化以及GTP结合蛋白激活的总体速率在多大程度上可以依赖于结合频率。我们在此根据相遇偶联模型对激动剂浓度与环化酶反应曲线进行定量分析，该模型明确将激动剂结合频率、相遇频率和相遇持续时间作为参数。基本结果是，该模型在定量上与S49细胞中受体介导的腺苷酸环化酶激活的浓度与反应曲线一致。还表明，该模型与关于拮抗剂以依赖于拮抗剂结合频率的方式抑制激动剂刺激的环化酶激活的差异效应的数据一致。
