TY - JOUR T1 - Agonist-biased signalling at the histamine H<sub>4</sub> receptor: JNJ7777120 recruits beta-arrestin without activating G proteins JF - Molecular Pharmacology JO - Mol Pharmacol DO - 10.1124/mol.110.068395 SP - mol.110.068395 AU - Elizabeth M Rosethorne AU - Steven J Charlton Y1 - 2010/12/06 UR - http://molpharm.aspetjournals.org/content/early/2010/12/06/mol.110.068395.abstract N2 - The Gi/o-coupled histamine H4 receptor is highly expressed in haemopoietic cells and is a promising new target for the treatment of chronic inflammatory diseases. JNJ7777120 has been described as a selective antagonist at the H4 receptor and is widely used to characterise the physiological role of the H4 receptor. We have investigated the pharmacological properties of JNJ7777120 using two distinct downstream signalling readouts, G protein activation and β-arrestin recruitment. The H4 receptor agonists histamine and clobenpropit, but not JNJ7777120, were both able to induce [35S]-GTPγS binding in membranes prepared from U2OS-H4 cells. Thioperamide, a dual H3/H4 receptor antagonist, and JNJ7777120 were both able to inhibit the [35S]-GTPγS binding induced by clobenpropit. Agonists and antagonists specific for other members of the histamine receptor family had no effect in this assay format. Histamine and clobenpropit increased β-arrestin recruitment to the H4 receptor in a concentration-dependent manner. This β-arrestin recruitment could be inhibited by pre-incubation with thioperamide. Surprisingly, pre-incubation with the H4-selective antagonist JNJ7777120 did not antagonise, but rather potentiated the response to histamine. JNJ7777120 treatment alone resulted in an increase in β--arrestin recruitment, which again could be inhibited by pre-incubation with thioperamide. Schild analysis demonstrated competitive antagonism between thioperamide and both clobenpropit and JNJ7777120. Histamine and clobenpropit had comparable potencies for both [35S]-GTPγS binding β-arrestin recruitment, suggesting little difference in the levels of receptor reserve between the two assays. In conclusion, we have demonstrated that JNJ7777120 recruits β-arrestin to the H4 receptor, independent of G protein activation. ER -