INVOLVEMENT OF PROTEIN-KINASE-C IN HOMOLOGOUS DESENSITIZATION OF HISTAMINE-EVOKED SECRETORY RESPONSES IN RAT CHROMAFFIN CELLS

The secretory responses in rat adrenal chromaffin cells to histamine H -1 receptor stimulation desensitize during repetitive stimulation. The rate of development of this desensitization was slowed by Ro 31-8220, a protein kinase C (PKC) inhibitor. Ro 31-8220 also reversed part of the desensitization which had been induced by earlier histamine stimul ation. Phorbol 12,13-dibutyrate (PDBu), an activator of protein kinase C, inhibited histamine-evoked catecholamine (CA) secretion almost com pletely. The inhibitory effect of PDBu on the H-1-receptor-mediated se cretory response was antagonized by Ro 31-8220. Histamine induced [Ca2 +](i) increases due to Ca2+ entry and Ca2+ release from intracellular Ca2+ stores in fura-2-loaded adrenal medullary cells. These [Ca2+](i) increases were abolished in PDBu-treated cells. These results suggest that the activation of PKC following histamine H-1 receptor stimulatio n plays a significant role in the process of homologous desensitizatio n of histamine-evoked secretory responses in rat chromaffin cells, thr ough modulation by PKC of H-1 receptors and/or GTP-binding proteins co upled with H-1 receptors. (C) 1997 Elsevier Science B.V.