Quantitative aspects of drug-receptor interactions: II. The role of Ca mem2+ in desensitization and spasmolytic activity

• Published in: Journal of theoretical biology Vol. 40; no. 1; pp. 155 - 172
• 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)90169-0

The implications of the basic model of agonist-receptor interactions outlined in paper I † † See previos paper, referred to as paper I. are further examined with specific reference to the role of Ca mem 2+ in desensitization and the action of spasmolytic agents (papaverine). Using the same series of 1, 3-dioxolane agonists it has been found that only the full agonists produce desensitization and that this process is enhanced by high agonist and low Ca ext 2+ concentrations. It is proposed that one form of desensitization is derived from a critical reduction in [Ca mem 2+] leading to a membrane conformational change to an inactive state. The selectivity of papaverine, chosen as a typical spasmolytic agent, for the tonic component of response is only seen with full agonists at high concentrations. It is suggested that the same factor controlling desensitization (Ca mem 2+) also determines the selectivity of papaverine action: papaverine is proposed to bind preferentially to Ca 2+-depleted membrane states. The basic conclusion from both papers is that receptor activation consists of a transition between Ca 2+-associated and Ca 2+-dissociated membrane states and that the extent of this activation determines the properties of many agonist and antagonist drugs.