Cloning, Expression, and Pharmacological Characterization of a Novel Human Histamine Receptor

Abstract

Using a genomics-based reverse pharmacological approach for screening orphan G-protein coupled receptors, we have identified and cloned a novel high-affinity histamine receptor. This receptor, termed AXOR35, is most closely related to the H3 histamine receptor, sharing 37% protein sequence identity. A multiple responsive element/cyclic AMP-responsive element-luciferase reporter assay was used to identify histamine as a ligand for AXOR35. When transfected into human embryonic kidney 293 cells, the AXOR35 receptor showed a strong, dose-dependent calcium mobilization response to histamine and H3 receptor agonists including imetit and immepip. Radioligand binding confirmed that the AXOR35 receptor was a high-affinity histamine receptor. The pharmacology of the AXOR35 receptor was found to closely resemble that of the H3 receptor; the major difference was that (R)-alpha-methylhistamine was a low potency agonist of the AXOR35 receptor. Thioperamide is an antagonist at AXOR 35. Expression of AXOR35 mRNA in human tissues is highest in peripheral blood mononuclear cells and in tissues likely to contain high concentrations of blood cells, such as bone marrow and lung. In situ hybridization analysis of a wide survey of mouse tissues showed that mouse AXOR35 mRNA is selectively expressed in hippocampus. The identification and localization of this new histamine receptor will expand our understanding of the physiological and pathological roles of histamine and may provide additional opportunities for pharmacological modification of these actions.

Role of H3-Receptor-Mediated Signaling in Anxiety and Cognition in Wild-Type and Apoe–/– Mice

“…Similarly, by altering the lipid environment, apoE deficiency may reduce the total number of H 3 receptor binding sites available for ligand binding in the amygdala, hippocampus, and cortex. Recently, the H 4 receptor was cloned and characterized (Nakamura et al, 2000;Oda et al, 2000;Liu et al, 2001;Morse et al, 2001;Nguyen et al, 2001;Zhu et al, 2001). To determine whether H 4 signaling was involved in the observed effects on object recognition, we tested mice treated with the H 4 receptor agonist and H 3 receptor antagonist clobenpropit (Oda et al, 2000).…”

“…Wild-type and Apoe -/-mice (3-5 months old) received saline, thioperamide, or clobenpropit during the training (day 4) and retention (day 5) sessions. The recently cloned H 4 receptor (Oda et al, 2000;Liu et al, 2001;Morse et al, 2001;Nguyen et al, 2001;Zhu et al, 2001) was found to have an affinity for H 3 -specific ligands. To rule out the possible contribution of the H 4 receptor to the effects of thioperamide, we also treated wild-type and Apoe -/-mice with clobenpropit, None of the differences between wild-type and Apoe -/-mice were significant.…”

Rôle de l’histamine et des récepteurs histaminiques dans la pathogenèse du paludisme

“…Il est exprimé dans les fibres nerveuses et sa stimulation par l'histamine diminue la libération d'histamine mais aussi d'autres neuromédiateurs [15]. L'activation du récepteur H4, exprimé par les cellules mononucléées et les lymphocytes T CD4 + et CD8 + [16], inhibe la production de la chimiokine CCL2 engendrant ainsi une réduction du recrutement des monocytes [17]. L'histamine fait l'objet de recherches intenses et son étude est capitale pour mieux comprendre et traiter l'allergie.…”

CC12, a high-affinity ligand for [3H]cimetidine binding, is an improgan antagonist

“…The negligible activity of CC12 at H 1 and H 2 receptors is consistent with this conclusion. At H 4 receptors, both improgan (Zhu et al, 2001) and CC12 have low affinity. The affinity of CC12 for the H 3 receptor is noteworthy (K i = 50 nM), and consistent with H 3 pharmacophore studies (Esbenshade et al, 2006).…”