Rabbit Anti-Human HRH2 Polyclonal antibody

Cholangiopathies are characterized by the heterogeneous proliferation of different-sized cholangiocytes. Large cholangiocytes proliferate by a cAMP-dependent mechanism. The function of small cholangiocytes may depend on the activation of inositol trisphosphate (IP3)/Ca2+-dependent signaling pathways; however, data supporting this speculation are lacking. Four histamine receptors exist (HRH1, HRH2, HRH3, and HRH4). In several cells: 1) activation of HRH1 increases intracellular Ca2+ concentration levels; and 2) increased [Ca2+](i) levels are coupled with calmodulin-dependent stimulation of calmodulin-dependent protein kinase (CaMK) and activation of cAMP-response element binding protein (CREB). HRH1 agonists modulate small cholangiocyte proliferation by activation of IP3/Ca2+-dependent CaMK/CREB. We evaluated HRH1 expression in cholangiocytes. Small and large cholangiocytes were stimulated with histamine trifluoromethyl toluidide (HTMT dimaleate; HRH1 agonist) for 24-48 h with/without terfenadine, BAPTA/AM, or W7 before measuring proliferation. Expression of CaMK I, II, and IV was evaluated in small and large cholangiocytes. We measured IP3, Ca2+ and cAMP levels, phosphorylation of CaMK I, and activation of CREB (in the absence/presence of W7) in small cholangiocytes treated with HTMT dimaleate. CaMK I knockdown was performed in small cholangiocytes stimulated with HTMT dimaleate before measurement of proliferation and CREB activity. Small and large cholangiocytes express HRH1, CaMK I, and CaMK II. Small (but not large) cholangiocytes proliferate in response to HTMT dimaleate and are blocked by terfenadine (HRH1 antagonist), BAPTA/AM, and W7. In small cholangiocytes, HTMT dimaleate increased IP3/Ca2+ levels, CaMK I phosphorylation, and CREB activity. Gene knockdown of CaMK I ablated the effects of HTMT dimaleate on small cholangiocyte proliferation and CREB activation. The IP3/Ca2+/CaMK I/CREB pathway is important in the regulation of small cholangiocyte function.

Histamine is a biologically active substance of local effect, but is involved in the regulation of different processes in the body, including the pathogenesis of diseases. In the present review, molecular genetic, clinical, and experimental studies on the role of histamine and key genes of its metabolism in the pathogenesis of diseases are summarized. Data on associated polymorphic variants (30 SNPs, 1 CNV) of key histamine metabolism genes with multifactorial diseases are given, including HDC (involved in the synthesis of histamine), HNMT, AOC1, MAOB, ALDH7A1 (involved in the processes of histamine degradation), and HRH1, HRH2, HRH3, HRH4 (histamine receptors): associations were established with allergic and oncological diseases, diseases of nervous and cardiovascular systems, gastrointestinal tract, metabolic disorders, etc. A nonrandomness of established associations of histamine metabolic pathway genes with pathological conditions is supported by clinical observations and experimental studies performed on model objects and cell lines. Moreover, according to clinical and experimental data, a wider range of pathological conditions in which risk structural and functional peculiarities of key histamine metabolic pathway genes will make a certain contribution can be expected. The questions of the complexity of determining the significance of histamine level and structural and functional peculiarities of histamine metabolic pathway genes in terms of a positive/negative effect on the body, as well as some possible reasons for inconsistency of association studies performed in different ethnoterritorial groups, are discussed.