Quantitative aspects of drug-receptor interactions. II. The role of Ca_mem²⁺ in desensitization and spasmolytic activity

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_mem²⁺ 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_ext²⁺ concentrations. It is proposed that one form of desensitization is derived from a critical reduction in [Ca_mem²⁺] 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_mem²⁺) also determines the selectivity of papaverine action: papaverine is proposed to bind preferentially to Ca²⁺-depleted membrane states. The basic conclusion from both papers is that receptor activation consists of a transition between Ca²⁺-associated and Ca²⁺-dissociated membrane states and that the extent of this activation determines the properties of many agonist and antagonist drugs.