Role of protein kinase Calpha in signaling from the histamine H(1) 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 PKCalpha and PKCdelta were down-regulated by prolonged treatment with phorbol esters. Of the two isoforms that were down-regulated, only protein kinase Calpha was translocated to CHO-H1 cell membranes after stimulation with either histamine or phorbol esters. The PKC inhibitor Gö 6976, which inhibits PKCalpha but not PKCdelta, 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 PKCalpha was the mitogen-activated protein kinase pathway. These data suggest that the histamine H(1) receptor can signal to the nucleus via PKCalpha after activation of phospholipase Cbeta.
Megson
A C
AC
Institute of Cell Signalling and School of Biomedical Sciences, Medical School, Queen's Medical Centre, Nottingham, United Kingdom.
Walker
E M
EM
Hill
S J
SJ
D000818:Animals; D016466:CHO Cells; D002118:Calcium / Q000378:metabolism; D002467:Cell Nucleus / Q000502:physiology*; D006224:Cricetinae; D000242:Cyclic AMP / Q000378:metabolism; D015870:Gene Expression; D007527:Isoenzymes / Q000502:physiology*; D048369:MAP Kinase Kinase 1; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D011493:Protein Kinase C / Q000502:physiology*; D051571:Protein Kinase C-alpha; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics / Q000378:metabolism; D011969:Receptors, Histamine H1 / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*
D007527:Isoenzymes; D016760:Proto-Oncogene Proteins c-fos; D011969:Receptors, Histamine H1; D000242:Cyclic AMP; D017346:Protein Serine-Threonine Kinases; D011493:Protein Kinase C; D051571:Protein Kinase C-alpha; D048369:MAP Kinase Kinase 1; D020929:Mitogen-Activated Protein Kinase Kinases; D002118:Calcium