Heterologous desensitization of muscarinic receptors by P-2Z purinoceptorsin rat parotid acinar cells

We studied the heterologous desensitization of muscarinic receptors by ATP in fura-2-loaded rat parotid acinar cells. Exposure to ATP or 3'-o-(4-benzo yl) benzoyl-ATP shortened the duration and decreased the magnitude of acety lcholine-induced Ca2+ release from intracellular Ca2+ stores in a dose-depe ndent manner. The shortening was observed only in an early stage of desensi tization (within 20 s), whereas the decrease in the magnitude of the respon se was dependent upon the time the cells were exposed to the nucleotides. A tropine induced a profound shortening during the progressive decrease in th e magnitude of acetylcholine-induced Ca2+ release. 3'-o-(4-Benzoyl) benzoyl -ATP did not induce an increase in the cytosolic Ca2+ concentration when th e cells were incubated in the Ca2+- and Na+-free medium, but it did induce a strong desensitization of muscarinic receptors. The specific protein kina se C inhibitor bisindoylmaleimide resensitized the 3'-o-(4-benzoyl) benzoyl -ATP-treated muscarinic receptors. Phorbol 12-myristate 13-acetate potentia ted the desensitization of muscarinic receptors. Ceramides that prevent the activation of phospholipase D resensitized the 3'-o-(4-benzoyl) benzoyl-AT P-treated muscarinic receptors. These results suggest that ATP, acting thro ugh P-2Z purinoceptor-mediated phospholipase D, may produce a Ca2+-independ ent protein kinase C. Heterologous desensitization of muscarinic receptors by protein kinase C may shorten the duration and decrease the magnitude of acetylcholine-induced Ca2+ release. (C) 1999 Elsevier Science B.V. All righ ts reserved.