Purinergic signaling in the peripheral vestibular system

Abstract

The inner ear comprises the cochlea and vestibular system, which detect sound and acceleration stimulation, respectively. The function of the inner ear is regulated by ion transport activity among sensory epithelial cells, neuronal cells, non-sensory epithelial cells, and luminal fluid with a unique ionic composition of high [K⁺] and low [Na⁺], which enables normal hearing and balance maintenance. One of the important mechanisms regulating ion transport in the inner ear is purinergic signaling. Various purinergic receptors are distributed throughout inner ear epithelial cells and neuronal cells. To date, most studies have focused on the role of purinergic receptors in the cochlea, and few studies have examined these receptors in the vestibular system. As purinergic receptors play an important role in the cochlea, they would likely do the same in the vestibular system, which is fairly similar to the cochlea in cellular structure and function. Based on available studies performed to date, purinergic signaling is postulated to be involved in the regulation of ion homeostasis, protection of hair cells, otoconia formation, and regulation of electrical signaling from the sensory epithelium to vestibular neurons. In this review, the distribution and roles of purinergic receptors in the peripheral vestibular system are summarized and discussed.

Keywords: Inner ear; Purinergic receptors; Saccule; Semicircular canal; Utricle; Vestibular system.

Fig. 1

Schematic of the functionally proven distribution of P2 receptors in the peripheral vestibular system. a Inner ear structure, which consists of cochlear and vestibular system. SCC, semicircular canal; CC, common crus; U, utricle; S, saccule; VG, vestibular ganglion. b Structure and cation transport by epithelial cells of the semicircular canal ampulla. CU, cupula. c Structure and cation transport by epithelial cells of the utricle. Oc, otoconia; Ocm, otoconial membrane. d ATP-induced cation transport and release of intracellular Ca²⁺ stores via purinergic receptors in supporting cells, hair cells, and transitional cells. In type 1 and type 2 hair cells, cations are absorbed by apically located P2X receptors or non-selective cation channels activated by P2 receptors. Apical P2 receptors (perhaps P2Y receptors) and basolateral P2Y receptors (type of hair cell was not identified) induce intracellular [Ca²⁺] release. ATP induces efflux of intracellular K⁺ absorbed through mechanosensitive non-selective cation channels on hair cell cilia, non-selective cation channels, and/or P2X receptors in apical membrane via basolaterally located Ca²⁺-activated K⁺ channels by inducing P2 receptor–mediated intracellular [Ca²⁺] increase. In distal vestibular afferent nerve, P2Y receptors modulate neuronal firing rate. In the supporting cell, cations are absorbed apically through P2X₂ and P2X₄ receptors. Apical P2Y₂ or P2Y₄ receptors induce intracellular [Ca²⁺] release. Otopetrin 1 (OTOP1) increases Ca²⁺ influx via OTOP1 itself and/or interacting P2X receptors or other proteins. OTOP1 inhibits the activity of P2Y₂ or P2Y₄ receptors and regulates intracellular [Ca²⁺]. In transitional cells, cations are absorbed via P2X₂ and P2X₄ receptors. Red: transitional cells in the utricle, blue: transitional cells in the ampulla and utricle. e Intracellular Ca²⁺ release and Ca²⁺ influx in the vestibular ganglion. P2X_1-6 receptors may be involved in Ca²⁺ influx, but the specific type of P2X receptor was not identified. Intracellular Ca²⁺ release was likely to be mediated by P2Y receptors, but the type of P2Y receptors was not identified. f Regulation of K⁺ efflux from vestibular dark cells by P2Y₂ and P2Y₄ receptors. K⁺ efflux via KCNQ1/KCNE1 is presumed to be inhibited by apical P2Y₄ and basolateral P2Y₂ through the phosphorylation of the β-subunit of the apical K⁺ channel by protein kinase C or direct inhibition by increased intracellular Ca²⁺ concentrations or by altered levels of membrane phosphatidylinositol-4,5-bisphosphate. PKC, protein kinase C; DAG, diacylglycerol; IP3, inositol 1,4,5-trisphosphate. g P2Y₂ regulation of paracellular ion transport in the semicircular canal duct epithelium. P2Y₂ receptors decrease the resistance of paracellular tight junctions and increase the permeability of ions. The receptor may be involved in apical Na⁺ influx and Cl⁻ efflux, for which direct evidence was not provided. SCCDE, semicircular canal duct epithelium. The sky blue area on each figure represents endolymphatic space