Mepacrine blocks beta-adrenergic agonist-induced desensitization in astrocytoma cells.

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Abstract
C6 [rat] astrocytoma cells contain .beta.-adrenergic receptors coupled to adenylate cyclase. A 2-h exposure to l-isoproterenol results in an 80% decrease in cyclic[c]AMP production in response to a subsequent challenge by l-isoproterenol (desensitization). This loss in responsiveness is paralleled by a 20-30% decrease in the apparent number of .beta.-adrenergic receptors and by increased release of arachidonic acid into the medium. The increased release of arachidonic acid is caused by the action of phospholipase A2 (phosphatide-2-acylhydrolase, EC 3.1.1.4) and corresponds to increased turnover of methylated phospholipids. Mepacrine and tetracaine, inhibitors of this phospholipase A2, are able to block l-isoproterenol-induced desensitization of cAMP production and the decrease in .beta.-adrenergic receptors. Mellitin and phorbol ester, 2 activators of phospholipase A2, when preincubated with the cells cause a decreased cAMP response of the cells to l-isoproterenol. The activation of phospholipase A2 in the local domain of the .beta.-adrenergic receptor may be involved in desensitization.