A POSSIBLE MECHANISM OF ACTION OF CALCIUM AND SOME PSYCHOTOMIMETIC AGENTS ON MEMBRANES

Journal/Book: Reprinted from Nature Vol. 197 No. 4865 pp. 367-368 January 26 1963. 1963;

Abstract: Departments of Psychiatry and Biochemistry University of Illinois College of Medicine Chicago IN the course of investigating the mechanism of action of a group of anticholinergic psychotomimetic agents it was observed that the agents seemed to influence those properties of excitable tissues that were particularly sensitive to a depletion of Ca2+. The importance of Ca2+ in the maintenance of excitability in nerve and muscle has been recognized since 1883 1 but it was only recently that there has been a revival of interest in it following the observation of Hodgkin and Keynes2 that an increased influx of Ca2+ accompanied excitation of the squid giant axon. This article discusses the types of Ca2+-dependent systems in excitable tissues which are influenced by the agents and the possible mechanisms involved. The chemistry and pharmacology of the agents concerned within the present study are described elsewhere3. They encompass a wide variety of esters of heterocyclic imino and di-imino alcohols and substituted glycolic and other carboxylic acids. An example of this class and that utilized in the present investigation is N-methyl-2-pyrrolidyl methyl cyclopentylphenyl glycolate (PMCG) Resting potentials were recorded in single fibres of freshly dissected frog sartorius muscles with the glass capillary microelectrode (Ling-Gerard type) filled with 3 M potassium chloride and having a resistente of 20 megohms. A pair of muscles were first soaked in Ringer´s solution for 30 min before the resting potentials of each muscle were determined. One muscle was then transferred to a solution of calcium-free Ringers solution and the resting potentials were measured after spontaneous twitching ceased 40 min later. The experimental muscle was simultaneously transferred to a calcium-free Ringer solution containing 10-4 M PMCG and the resting potential also recorded 40 min later. Comparable experiments were conducted in calcium-free Ringer's containing 4 mM EDTA. A set of experiments was performed where 10-4 M PMCG was present in the test solution prior to the immersion of the experimental muscle. When frog muscles are transferred from a Ringers to a calcium-free solution there is a rapid drop in the intra-fibrillar resting potential which results in spontaneous twitching or fasciculation of the muscle. ... ___MH

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