PT - JOURNAL ARTICLE AU - Timothy W. Lovenberg AU - Barbara L. Roland AU - Sandy J. Wilson AU - Xiaoxia Jiang AU - Jayashree Pyati AU - Arne Huvar AU - Michael R. Jackson AU - Mark G. Erlander TI - Cloning and Functional Expression of the Human Histamine H<sub>3</sub> Receptor AID - 10.1124/mol.55.6.1101 DP - 1999 Jun 01 TA - Molecular Pharmacology PG - 1101--1107 VI - 55 IP - 6 4099 - http://molpharm.aspetjournals.org/content/55/6/1101.short 4100 - http://molpharm.aspetjournals.org/content/55/6/1101.full SO - Mol Pharmacol1999 Jun 01; 55 AB - Histamine regulates neurotransmitter release in the central and peripheral nervous systems through H3 presynaptic receptors. The existence of the histamine H3 receptor was demonstrated pharmacologically 15 years ago, yet despite intensive efforts, its molecular identity has remained elusive. As part of a directed effort to discover novel G protein-coupled receptors through homology searching of expressed sequence tag databases, we identified a partial clone (GPCR97) that had significant homology to biogenic amine receptors. The GPCR97 clone was used to probe a human thalamus library, which resulted in the isolation of a full-length clone encoding a putative G protein-coupled receptor. Homology analysis showed the highest similarity to M2 muscarinic acetylcholine receptors and overall low homology to all other biogenic amine receptors. Transfection of GPCR97 into a variety of cell lines conferred an ability to inhibit forskolin-stimulated cAMP formation in response to histamine, but not to acetylcholine or any other biogenic amine. Subsequent analysis revealed a pharmacological profile practically indistinguishable from that for the histamine H3 receptor. In situ hybridization in rat brain revealed high levels of mRNA in all neuronal systems (such as the cerebral cortex, the thalamus, and the caudate nucleus) previously associated with H3 receptor function. Its widespread and abundant neuronal expression in the brain highlights the significance of histamine as a general neurotransmitter modulator. The availability of the human H3 receptor cDNA should greatly aid in the development of chemical and biological reagents, allowing a greater appreciation of the role of histamine in brain function.