Among the four G protein-coupled receptors (H-H) identified as mediators of the biologic effects of histamine, the H receptor (HR) is distinguished for its almost exclusive expression in the nervous system and the large variety of isoforms generated by alternative splicing of the corresponding mRNA. Additionally, it exhibits dual functionality as autoreceptor and heteroreceptor, and this enables HRs to modulate the histaminergic and other neurotransmitter systems. The cloning of the HR cDNA in 1999 by Lovenberg et al. allowed for detailed studies of its molecular aspects. In this work, we review the characteristics of the HR, namely, its structure, constitutive activity, isoforms, signal transduction pathways, regional differences in expression and localization, selective agonists, antagonists and inverse agonists, dimerization with other neurotransmitter receptors, and the main presynaptic and postsynaptic effects resulting from its activation. The HR has attracted interest as a potential drug target for the treatment of several important neurologic and psychiatric disorders, such as Alzheimer and Parkinson diseases, Gilles de la Tourette syndrome, and addiction.

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In stably-transfected human neuroblastoma SH-SY5Y cells, we have compared the effect of activating two isoforms of 445 and 365 amino acids of the human histamine H receptor (hHR and hHR) on [S]-GTPγS binding, forskolin-induced cAMP formation, depolarization-induced increase in the intracellular concentration of Ca ions ([Ca]i) and depolarization-evoked [H]-dopamine release. Maximal specific binding (B) of [H]-N-methyl-histamine to cell membranes was 953 ± 204 and 555 ± 140 fmol/mg protein for SH-SY5Y-hHR and SH-SY5Y-hHR cells, respectively, with similar dissociation constants (K, 0.86 nM and 0.81 nM). The mRNA of the hHR isoform was 40.9 ± 7.9% of the hHR isoform. No differences in receptor affinity were found for the HR ligands histamine, immepip, (R)(-)-α-methylhistamine (RAMH), A-331440, clobenpropit and ciproxifan. Both the stimulation of [S]-GTPγS binding and the inhibition of forskolin-stimulated cAMP accumulation by the agonist RAMH were significantly larger in SH-SY5Y-hHR cells ([S]-GTPγS binding, 158.1 ± 7.5% versus 136.5 ± 3.6% for SH-SY5Y-hHR cells; cAMP accumulation, -74.0 ± 4.9% versus -43.5 ± 5.3%), with no significant effect on agonist potency. In contrast, there were no differences in the efficacy and potency of RAMH to inhibit [H]-dopamine release evoked by 100 mM K (-18.9 ± 3.0% and -20.5 ± 3.3%, for SH-SY5Y-hHR and SH-SY5Y-hHR cells), or the inhibition of depolarization-induced increase in [Ca]i (S2/S1 ratios: parental cells 0.967 ± 0.069, SH-SY5Y-hHR cells 0.639 ± 0.049, SH-SY5Y-hHR cells 0.737 ± 0.045). These results indicate that in SH-SY5Y cells, hHR and hHR isoforms regulate in a differential manner the signaling pathways triggered by receptor activation.

These data indicate a direct inhibitory effect of clobenpropit on catecholamine transport.

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