Differential activation of dual signaling responses by human H1 and H2 histamine receptors.
Stimulation of human H1 and H2-histamine receptors (HRs) primarily activates signaling pathways to increase intracellular calcium [Ca2+]i and cyclic AMP (cAMP), respectively. Activation of H2-HR in human embryonic kidney (HEK) cells by histamine and dimaprit increases both cAMP formation and [Ca2+]i, as determined by cAMP-scintillation proximity assays and fluorescence imaging plate reader (FLIPR) assays. In HEK cells expressing relatively high levels of H2-HR (Bmax=26 pmol/mg protein), histamine and dimaprit are full agonists in eliciting cAMP responses with pEC50 values of 9.30 and 7.72 that are 1000-fold more potent than their respective pEC50 values of 6.13 and 4.91 for increasing [Ca2+]i. The agonist potencies decrease for both responses at lower H2-HR density (5 pmol/mg protein) and dimaprit exhibits partial agonist behavior for the [Ca2+]i response. The inverse agonists ranitidine and cimetidine more potently inhibit cAMP production in the higher expressing H2-HR line. Histamine also activated both signaling pathways via human H1-HRs highly expressed (Bmax=17 pmol/mg protein) in HEK cells, with a 1000-fold greater potency for [Ca2+]i vs. cAMP responses (pEC50=7.86 and 4.82, respectively). These studies demonstrate a markedly different potency for activation of multiple signaling pathways by H1- and H2-HRs that may contribute to the selectivity of histamine responses in vivo.
Esbenshade
Timothy A
TA
Neuroscience Research, Global Pharmaceutical Research Division, Abbott Laboratories, Abbott Park, Illinois 60064, USA. tim.esbenshade@abbott.com
Kang
Chae Hee
CH
Krueger
Kathleen M
KM
Miller
Thomas R
TR
Witte
David G
DG
Roch
Jean M
JM
Masters
Jeffrey N
JN
Hancock
Arthur A
AA
D020013:Calcium Signaling / Q000187:drug effects; D002460:Cell Line; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism; D017259:Dimaprit / Q000494:pharmacology; D006632:Histamine / Q000494:pharmacology; D017442:Histamine Agonists / Q000494:pharmacology; D006801:Humans; D007700:Kinetics; D011969:Receptors, Histamine H1 / Q000235:genetics / Q000378:metabolism*; D011970:Receptors, Histamine H2 / Q000235:genetics / Q000378:metabolism*; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014162:Transfection
D017442:Histamine Agonists; D011969:Receptors, Histamine H1; D011970:Receptors, Histamine H2; D011994:Recombinant Proteins; D005576:Colforsin; D006632:Histamine; D000242:Cyclic AMP; D017259:Dimaprit