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CELLULAR AND MOLECULAR

An 80-Amino Acid Deletion in the Third Intracellular Loop of a Naturally Occurring Human Histamine H₃ Isoform Confers Pharmacological Differences and Constitutive Activity

Leiden/Amsterdam Center for Drug Research, Department of Medicinal Chemistry, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands (G.B., P.v.M., R.A.B., R.L.); and Neuroscience Research, Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, Illinois (K.M.K., T.R.M., J.L.B., B.R.E., D.G.W., M.I.S., M.D.C., A.A.H., T.A.E.)

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.

Address correspondence to: Dr. Rob Leurs, Leiden/Amsterdam Center for Drug Research, Department of Medicinal Chemistry, Vrije Universiteit Amsterdam, De Boelelaan 1083, 1081 HV Amsterdam, The Netherlands. E-mail: r.leurs{at}few.vu.nl