Discovery of Naturally Occurring Splice Variants of the Rat Histamine H3 Receptor That Act as Dominant-Negative Isoforms
Molecular Pharmacology. 2006-04-01; 69(4): 1194-1206
DOI: 10.1124/mol.105.019299
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Bakker RA(1), Lozada AF, van Marle A, Shenton FC, Drutel G, Karlstedt K,
Hoffmann M, Lintunen M, Yamamoto Y, van Rijn RM, Chazot PL, Panula P, Leurs R.
Author information:
(1)The Leiden/Amsterdam Center for Drug Research, Department of Medicinal
Chemistry, Vrije Universiteit Amsterdam, De Boelelaan 1083, 1081HV Amsterdam,
The Netherlands.
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 rH3A,
rH3B, and rH3C 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 (rH3D, rH3E, and rH3F) 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 rH3A receptor (rH3AR), detection of the
rH3D isoform using hemagglutinin antibodies revealed that the rH3D isoform
remains mainly intracellular. The expression of the rH3D-F splice variants,
however, modulates the cell surface expression-levels and subsequent functional
responses of the 7TM H3R isoforms. Coexpression of the rH3AR and the rH3D
isoforms resulted in the intracellular retention of the rH3AR and reduced rH3AR
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.
DOI: 10.1124/mol.105.019299
PMID: 16415177 [Indexed for MEDLINE]