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J. Biol. Chem., Vol. 282, Issue 14, 10690-10696, April 6, 2007

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Deafness and Stria Vascularis Defects in S1P₂ Receptor-null Mice^*

Mari Kono, Inna A. Belyantseva, Athanasia Skoura^¶, Gregory I. Frolenkov¹, Matthew F. Starost^||, Jennifer L. Dreier, Darcy Lidington^**, Steffen-Sebastian Bolz^**, Thomas B. Friedman, Timothy Hla^¶, and Richard L. Proia²

From the Genetics of Development and Disease Branch, NIDDK, National Institutes of Health, Bethesda, Maryland 20892, Laboratory of Molecular Genetics, NIDCD, National Institutes of Health, Rockville, Maryland 20850, ^¶Center for Vascular Biology, Department of Cell Biology, University of Connecticut Health Center, Farmington, Connecticut 06030-3501, ^||Division of Veterinary Resources, National Institutes of Health, Bethesda, Maryland 20892, ^**Department of Physiology and Heart and Stroke/Richard Lewar Centre of Excellence, University of Toronto, Toronto, Ontario M5S 1A8, Canada, and Otolaryngology Branch, NIDCD, National Institutes of Health, Rockville, Maryland 20850

The S1P₂ receptor is a member of a family of G protein-coupled receptors that bind the extracellular sphingolipid metabolite sphingosine 1-phosphate with high affinity. The receptor is widely expressed and linked to multiple G protein signaling pathways, but its physiological function has remained elusive. Here we have demonstrated that S1P₂ receptor expression is essential for proper functioning of the auditory and vestibular systems. Auditory brainstem response analysis revealed that S1P₂ receptor-null mice were deaf by one month of age. These null mice exhibited multiple inner ear pathologies. However, some of the earliest cellular lesions in the cochlea were found within the stria vascularis, a barrier epithelium containing the primary vasculature of the inner ear. Between 2 and 4 weeks after birth, the basal and marginal epithelial cell barriers and the capillary bed within the stria vascularis of the S1P₂ receptor-null mice showed markedly disturbed structures. JTE013, an S1P₂ receptor-specific antagonist, blocked the S1P-induced vasoconstriction of the spiral modiolar artery, which supplies blood directly to the stria vascularis and protects its capillary bed from high perfusion pressure. Vascular disturbance within the stria vascularis is a potential mechanism that leads to deafness in the S1P₂ receptor-null mice.

Received for publication, September 26, 2006 , and in revised form, February 5, 2007.

^* This research was supported by the Intramural Research Program of the NIDDK and NIDCD, National Institutes of Health (NIH) and by NIH Grants PO1-HL-70694 and R37-HL-67330 (to T. H.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Present address: Department of Physiology, University of Kentucky, Lexington, KY 40536.

² To whom correspondence should be addressed: NIDDK, National Institutes of Health, Bethesda, MD 20892-1821. Tel.: 301-496-4391; Fax: 301-496-0839; E-mail: proia{at}nih.gov.

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