Role of protein kinase Cα in signaling from the histamine H1 receptor to the nucleus

Stimulation of histamine H-1 receptors produced a marked activation of inositol phospholipid hydrolysis, intracellular calcium mobilization, and stimulation of the c-fos promoter in CHO-H1 cells expressing the H-1 receptor at a level of 3 pmol/mg protein. The latter response was determined using a luciferase-based reporter gene (pGL3). This response to histamine was not sensitive to inhibition by pertussis toxin but could be completely attenuated by the protein kinase C (PKC) inhibitor Ro-31-8220, or by 24-h pretreatment with the phorbol esters phorbol 12,13-dibutyrate or phorbol-12-myristate-13-acetate. Several isoforms of PKC can be detected in CHO-H1 cells (alpha, delta, epsilon, mu, iota, zeta) but only PKC alpha and PKC delta were down-regulated by prolonged treatment with phorbol esters. Of the two isoforms that were down-regulated, only protein kinase C alpha was translocated to CHO-H1 cell membranes after stimulation with either histamine or phorbol esters. The PKC inhibitor Go 6976, which inhibits PKC alpha but not PKC delta, was also able to significantly attenuate the c-fos-luciferase response to histamine. The mitogen-activated protein kinase kinase inhibitor PD 98059 markedly inhibited the response to histamine, suggesting that the likely major target for PKC alpha was the mitogen-activated protein kinase pathway. These data suggest that the histamine H-1 receptor can signal to the nucleus via PKC alpha after activation of phospholipase C beta.