A 80 AMINO ACID DELETION IN THE THIRD INTRACELLULAR LOOP OF A NATURALLY OCCURRING HUMAN HISTAMINE H-3 ISOFORM CONFERS PHARMACOLOGICAL DIFFERENCES AND CONSTITUTIVE ACTIVITY

In this article, we pharmacologically characterized two naturally occurring human histamine H-3 receptor (hH(3)R) isoforms, hH(3)R(445) and hH(3)R(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 hH(3)R( 365) is differentially expressed compared with the hH(3)R(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 hH(3)R(365) compared with the hH(3)R(445) in both guanosine-5'-O-(3-[S-35]thio) triphosphate binding and cAMP assays, likely explaining the observed differences in hH(3)R 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.