RT Journal Article SR Electronic T1 Cloning and Functional Expression of the Human Histamine H3 Receptor JF Molecular Pharmacology JO Mol Pharmacol FD American Society for Pharmacology and Experimental Therapeutics SP 1101 OP 1107 DO 10.1124/mol.55.6.1101 VO 55 IS 6 A1 Timothy W. Lovenberg A1 Barbara L. Roland A1 Sandy J. Wilson A1 Xiaoxia Jiang A1 Jayashree Pyati A1 Arne Huvar A1 Michael R. Jackson A1 Mark G. Erlander YR 1999 UL http://molpharm.aspetjournals.org/content/55/6/1101.abstract 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.