Quantitative aspects of drug-receptor interactions: I. Ca 2+ and cholinergic receptor activation in smooth muscle: A basic model for drug-receptor interactions

• Published in: Journal of theoretical biology Vol. 40; no. 1; pp. 125 - 154
• Main Authors: Chang, K.-J., Triggle, D.J.
• Format: Journal Article
• Language: English
• Published: Elsevier Ltd 1973
• ISSN: 0022-5193; 1095-8541
• DOI: 10.1016/0022-5193(73)90168-9

An attempt has been made to devise a general model of drug-receptor interactions as it relates to the initiation of mechanical responses. A key feature of this model is the regulatory role played by membrane-bound Ca 2+ (Ca mem 2+). The effects on the mechanical responsiveness of guinea pig ileal longitudinal muscle of four muscarinic agonists derived from and including the highly active cis-2-methyl-4-dimethylaminomethyl-1, 3-dioxolane methiodide have been studied. The concentration-response (isotonic contraction) curves of these four agonists at normal Ca ext 2+-levels show evidence of cooperativity ( n H > 1) and this was found to increase dramatically with decreasing [Ca ext 2+]. A three step model has been proposed, based on that previously advanced by Hurwitz & Suria (1971), in which activation of the acetylcholine receptor initiates a Ca 2+ translocation mechanism supplying the contractile machinery with Ca 2+. Arguments are advanced to suggest that two sources of Ca 2+ are thus utilized: membrane-bound (Ca mem 2+) and free extracellular (Ca ext 2+), the former being responsible for the initial phasic contraction and the latter for the slower phase of contractile development. Analysis of the theoretical model shows that the cooperativity of the concentration-response relationships derives not from the initial agonist-receptor interaction but from the subsequently initiated Ca 2+ translocation step so that [Ca int 2+] ∝ [Ca ext 2+] n. The limiting value of n is found to be 6 and to be the same for agonists and partial agonists. According to this model intrinsic activity is determined by the linkage between the agonist-receptor complex and the Ca 2+ translocation process. The general findings of this work are discussed in terms of an equilibrium between Ca 2+-associated and Ca 2+-dissociated membrane states. The similarities to other Ca 2+ dependent processes are emphasized.