An 80-amino acid deletion in the third intracellular loop of a naturally occurring human histamine H₃ isoform confers pharmacological differences and constitutive activity

In this article, we pharmacologically characterized two naturally occurring human histamine H₃ receptor (hH₃R) isoforms, hH ₃R(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 H ₃R 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.