Adenosine and the auditory system

Abstract

Adenosine is a signalling molecule that modulates cellular activity in the central nervous system and peripheral organs via four G protein-coupled receptors designated A(1), A(2A), A(2B), and A(3). This review surveys the literature on the role of adenosine in auditory function, particularly cochlear function and its protection from oxidative stress. The specific tissue distribution of adenosine receptors in the mammalian cochlea implicates adenosine signalling in sensory transduction and auditory neurotransmission although functional studies have demonstrated that adenosine stimulates cochlear blood flow, but does not alter the resting and sound-evoked auditory potentials. An interest in a potential otoprotective role for adenosine has recently evolved, fuelled by the capacity of A(1) adenosine receptors to prevent cochlear injury caused by acoustic trauma and ototoxic drugs. The balance between A(1) and A(2A) receptors is conceived as critical for cochlear response to oxidative stress, which is an underlying mechanism of the most common inner ear pathologies (e.g. noise-induced and age-related hearing loss, drug ototoxicity). Enzymes involved in adenosine metabolism, adenosine kinase and adenosine deaminase, are also emerging as attractive targets for controlling oxidative stress in the cochlea. Other possible targets include ectonucleotidases that generate adenosine from extracellular ATP, and nucleoside transporters, which regulate adenosine concentrations on both sides of the plasma membrane. Developments of selective adenosine receptor agonists and antagonists that can cross the blood-cochlea barrier are bolstering efforts to develop therapeutic interventions aimed at ameliorating cochlear injury. Manipulations of the adenosine signalling system thus hold significant promise in the therapeutic management of oxidative stress in the cochlea.

Keywords: Adenosine; adenosine receptors; cochlea; deafness; hearing; noise; ototoxicity.; oxidative stress.

Fig. (1)

Mammalian cochlea. A) A cross section through the cochlea shows the central bony part (modiolus) which contains blood vessels and the auditory nerve, and the cochlear coiling divided into three compartments: scala vestibuli, scala media and scala tympani. Scala vestibuli and scala tympani contain perilymph. The organ of Corti (oc) sits on the basilar membrane and bathes in the potassium-rich fluid of the scala media (endolymph). B) Sensory tissues in the cochlea are located in the organ of Corti, secretory tissues is represented by the stria vascularis (sv) and primary auditory neurons are located in the spiral ganglion. High potassium content of the endolymph is maintained by secretion from the stria vascularis supported by the spiral ligament (sl). Afferent innervation of the inner and outer hair cells is provided by the spiral ganglion neurons (sgn). C) The organ of Corti comprises sensory cells (inner and outer hair cells) and a variety of supporting cells (Deiters’, Hensen’s and pillar cells). D) Surface preparation of the organ of Corti stained with phalloidin showing three rows of outer hair cells and one row of inner hair cells with the apically located stereocilia responsible for mechano-eletrical transduction. Abbreviations: IHC, inner hair cells; OHC, outer hair cells; rm, Reissner’s membrane; tm, tectorial membrane.

Fig. (2). Adenosine production, transport and metabolism.

The principal source of adenosine in extracellular fluid spaces is equilibrative nucleoside transport, with the net direction of transport being dependent upon the concentration gradient of adenosine across the cell membrane. Another source of adenosine is the activity of ectonucleotidases that breakdown extracellular ATP to adenosine. Intracellular adenosine is formed from S-adenosyl homocysteine via SAH hydrolase (pathway not shown). Enzymes contributing to the hydrolytic cascade that converts ATP to adenosine include NTPDases and ecto-5’- nucleotidase. Adenosine produced by extracellular ATP hydrolysis or transported from the intracellular compartment acts on adenosine receptors on target cells in a paracrine or autocrine fashion. Clearance of adenosine from the extracellular space is provided by nucleoside transporters. Intracellular adenosine is hydrolysed by adenosine deaminase to inosine, or phosphorylated to AMP by adenosine kinase (ADK), which appears to be a major regulator of ambient adenosine levels.