Differential activation of dual signaling responses by human H-1 and H-2 histamine receptors

摘要

Stimulation of human H-1 and H-2-histamine receptors (HRs) primarily activates signaling pathways to increase intracellular calcium [Ca2+](i) and cyclic AMP (cAMP), respectively. Activation Of H-2-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 H-2-HR (B-max=26 pmol/mg protein), histamine and dimaprit are full agonists in eliciting cAMP responses with pEC(50) values of 9.30 and 7.72 that are 1000-fold more potent than their respective pEC(50) values of 6.13 and 4.91 for increasing [Ca2+](i). The agonist potencies decrease for both responses at lower H-2-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 H-2-HR line. Histamine also activated both signaling pathways via human H (1)-HRs highly expressed (B-max = 17 pmol/mg protein) in HEK cells, with a 1000-fold greater potency for [Ca2+](i) VS. cAMP responses (pEC(50) = 7.86 and 4.82, respectively). These studies demonstrate a markedly different potency for activation of multiple signaling pathways by H-1- and H-2-HRs that may contribute to the selectivity of histamine responses in vivo. [References: 33]