Phosphoinositides histamine receptors

The characteristics of the four major classes of histamine receptors are summarized. Question marks indicate suggestions from the literature that have not been confirmed. AA, arachidonic acid DAG, diacylglycerol Iko,2+, calcium-activated potassium current IP3, inositol 1,4,5-trisphosphate NHE, sodium-proton exchange, PKC, protein kinase C NO, nitric oxide PTPLC, phosphoinositide-specific phospholipase C TXA2, thromboxane A2. Has brain-penetrating characteristics after systemic administration. 

Cherifi, Y., Pigeon, C., Le Romancer, M., Bado, A., Reyl-Desmars, F., Lewin, M.J.M., 1992. Purification of a histamine H3 receptor negatively coupled to phosphoinositide turnover in the human gastric cell line HGT1. J. Biol. Chem. 267, 25315-25320. 

Raymond JR, Albers FJ, Middleton JP, et al. 5-HT1A and histamine H, receptors in HeLa cells stimulate phosphoinositide hydrolysis and phosphate uptake via distinct G protein pools. J Biol Chem 1991 266 372-379. 

The H2 receptor is a 359-amino-acid protein in humans. It has some features similar to the Hi protein (e.g., N-terminal glycosylation sites) and phosphorylation sites in the C-terminal. An aspartic acid residue in the third transmembrane loop appears to be critical to agonist and antagonist binding, and threonine/aspartate and tyrosine/aspartate couples in the fifth transmembrane domain appear to be important for interaction of the imidazole part of the histamine molecule. It is positively coupled via Gas to activate adenylyl cyclase for synthesis of cyclic adenosine monophosphate (cAMP) as a second messenger. In some systems, it is coupled through Gq proteins to stimulate phospholipase C. It appears in some cells that other processes, such as breakdown of phosphoinositides, control of intracellular calcium ion levels, and phospholipase A2 activity, can be regulated by other cAMP-independent pathways. 

Whereas Hi receptors are involved with positive effects, H2 receptors appear to mainly mediate suppressive activities of histamine including gastric acid secretion, heart contraction, cell proliferation, differentiation, and some effects on the immune response. H2 receptors are coupled to the adenylate cyclase as well as the phosphoinositide second messenger systems via separate GTP-dependent mechanisms, but H2-dependent effects, particularly those of the central nervous system, are predominantly mediated through cAMP. It has been shown that receptor binding stimulates activation of c-Fos, c-Jun, PKC, and P70S6 kinase. Alternative signaling pathways have been reported (Fig. 3.7). These include a receptor-mediated increase in intracellular Ca and/or IP3 levels in HL-60 human promyelocytic leukemia cells and an increase in cAMP and inhibition of release of arachidonic acid in Chinese hamster ovary (CHO) cells transfected with rat cDNA and induced by calcium ionophore. 

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