TY - JOUR T1 - An 80-Amino Acid Deletion in the Third Intracellular Loop of a Naturally Occurring Human Histamine H<sub>3</sub> Isoform Confers Pharmacological Differences and Constitutive Activity JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 888 LP - 898 DO - 10.1124/jpet.107.127639 VL - 323 IS - 3 AU - Gerold Bongers AU - Kathleen M. Krueger AU - Thomas R. Miller AU - John L. Baranowski AU - Brian R. Estvander AU - David G. Witte AU - Marina I. Strakhova AU - Peter van Meer AU - Remko A. Bakker AU - Marlon D. Cowart AU - Arthur A. Hancock AU - Timothy A. Esbenshade AU - Rob Leurs Y1 - 2007/12/01 UR - http://jpet.aspetjournals.org/content/323/3/888.abstract N2 - In this article, we pharmacologically characterized two naturally occurring human histamine H3 receptor (hH3R) isoforms, hH3R(445) and hH3R(365). These abundantly expressed splice variants differ by a deletion of 80 amino acids in the intracellular loop 3. In this report, we show that the hH3R(365) is differentially expressed compared with the hH3R(445) and has a higher affinity and potency for H3R agonists and conversely a lower potency and affinity for H3R inverse agonists. Furthermore, we show a higher constitutive signaling of the hH3R(365) compared with the hH3R(445) in both guanosine-5′-O-(3-[35S]thio) triphosphate binding and cAMP assays, likely explaining the observed differences in hH3R pharmacology of the two isoforms. Because H3R ligands are beneficial in animal models of obesity, epilepsy, and cognitive diseases such as Alzheimer's disease and attention deficit hyperactivity disorder and currently entered clinical trails, these differences in H3R pharmacology of these two isoforms are of great importance for a detailed understanding of the action of H3R ligands. The American Society for Pharmacology and Experimental Therapeutics ER -