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Original Article

Discovery of Naturally Occurring Splice Variants of the Rat Histamine H₃ Receptor That Act as Dominant-Negative Isoforms

The Leiden/Amsterdam Center for Drug Research, Department of Medicinal Chemistry, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands (R.A.B., A.v.M., G.D., M.H., R.M.v.R., R.L.); the Department of Biology, Åbo Akademi University, Turku, Finland (A.F.L., K.K., M.L., Y.Y., P.P.); the Neuroscience Center and Institute of Biomedicine/Anatomy, University of Helsinki, Helsinki, Finland (P.P.); and the School of Biological and Biomedical Sciences, University of Durham, Durham, United Kingdom (F.C.S., P.L.C.)

Abstract

We described previously the cDNA cloning of three functional rat histamine H₃ receptor (rH₃R) isoforms as well as the differential brain expression patterns of their corresponding mRNAs and signaling properties of the resulting rH_3A, rH_3B, and rH_3C receptor isoforms (Mol Pharmacol 59:1–8). In the current report, we describe the cDNA cloning, mRNA localization in the rat central nervous system, and pharmacological characterization of three additional rH₃R splice variants (rH_3D, rH_3E, and rH_3F) that differ from the previously published isoforms in that they result from an additional alternative-splicing event. These new H₃R isoforms lack the seventh transmembrane (TM) helix and contain an alternative, putatively extracellular, C terminus (6TM-rH₃ isoforms). After heterologous expression in COS-7 cells, radioligand binding or functional responses upon the application of various H₃R ligands could not be detected for the 6TM-rH₃ isoforms. In contrast to the rH_3A receptor (rH_3AR), detection of the rH_3D isoform using hemagglutinin antibodies revealed that the rH_3D isoform remains mainly intracellular. The expression of the rH_3D-F splice variants, however, modulates the cell surface expression-levels and subsequent functional responses of the 7TM H₃R isoforms. Coexpression of the rH_3AR and the rH_3D isoforms resulted in the intracellular retention of the rH_3AR and reduced rH_3AR functionality. Finally, we show that in rat brain, the H₃R mRNA expression levels are modulated upon treatment with the convulsant pentylenetetrazole, suggesting that the rH₃R isoforms described herein thus represent a novel physiological mechanism for controlling the activity of the histaminergic system.

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

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