sphingosine-1-phosphate and Deafness

The S1P(2) 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 S1P(2) receptor expression is essential for proper functioning of the auditory and vestibular systems. Auditory brainstem response analysis revealed that S1P(2) 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 S1P(2) receptor-null mice showed markedly disturbed structures. JTE013, an S1P(2) 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 S1P(2) receptor-null mice.

Topics: Animals; Deafness; Epithelial Cells; Epithelium; Evoked Potentials, Auditory, Brain Stem; Lysophospholipids; Mice; Mice, Mutant Strains; Receptors, Lysosphingolipid; Sphingosine; Stria Vascularis; Time Factors

Hearing requires the transduction of vibrational forces by specialized epithelial cells in the cochlea known as hair cells. The human ear contains a finite number of terminally differentiated hair cells that, once lost by noise-induced damage or toxic insult, can never be regenerated. We report here that sphingosine 1-phosphate (S1P) signaling, mainly via activation of its cognate receptor S1P2, is required for the maintenance of vestibular and cochlear hair cells in vivo. Two S1P receptors, S1P2 and S1P3, were found to be expressed in the cochlea by reverse transcription-PCR and in situ hybridization. Mice that are null for both these receptors uniformly display progressive cochlear and vestibular defects with hair cell loss, resulting in complete deafness by 4 weeks of age and, with complete penetrance, balance defects of increasing severity. This study reveals the previously unknown role of S1P signaling in the maintenance of cochlear and vestibular integrity and suggests a means for therapeutic intervention in degenerative hearing loss.

Topics: Acoustic Stimulation; Aging; Animals; Cell Survival; Cochlea; Deafness; Exploratory Behavior; Hair Cells, Auditory; Hair Cells, Vestibular; Hearing; In Situ Hybridization; Lysophospholipids; Mice; Mice, Inbred C57BL; Mice, Knockout; Nerve Degeneration; Organ of Corti; Postural Balance; Receptors, Lysosphingolipid; Reflex, Startle; Reverse Transcriptase Polymerase Chain Reaction; Sensation Disorders; Sphingosine; Sphingosine-1-Phosphate Receptors; Spiral Ganglion; Vestibule, Labyrinth