Differential Activation of Dual Signaling Responses by Human H1and H2Histamine Receptors

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Abstract
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.