RAPID HETEROLOGOUS DESENSITIZATION OF MUSCARINIC AND THROMBIN RECEPTOR-MEDIATED PHOSPHOLIPASE-D ACTIVATION

Activation of the M(3) muscarinic receptor in 1321N1 human astrocytoma cells leads to increased phospholipase D (PLD)-catalyzed hydrolysis o f phosphatidylcholine, which is maximal within 1 min of exposure to ag onist. Studies examining the kinetics of phosphatidylethanol formation indicate that there is no further PLD activation beyond this time. Th rombin, a mitogen for quiescent 1321N1 cells, also activates PLD only transiently. The PLD response does not recover for up to 1 hr and cell s that have been exposed to carbachol or thrombin do not respond to su bsequent challenge with the heterologous agonist. In contrast to the d esensitization observed with agonists, phorbol-12-myristate-13-acetate induces a sustained stimulation of PLD. In addition, cells pretreated with carbachol or thrombin show a normal response to phorbol-12e-myri state-13-acetate, suggesting that