ReviewThe nicotinic receptor of cochlear hair cells: A possible pharmacotherapeutic target?
Graphical abstract
Targeting α9α10 nicotinic cholinergic receptors in pathologies of the auditory system.
Introduction
Sensory systems perform a series of common functions. Each system responds with some specificity to a stimulus from the surrounding world and employs some specialized receptor cells at the periphery to translate those stimuli into electrical signals that all neurons can understand. That initial electrical event begins the process by which the central nervous system constructs an orderly representation of for example, sounds, odors, tastes and visual objects. Thus, basic sound detection begins when sound waves strike the eardrum, which transmits that physical stimulus to the organ of Corti within the cochlea, the sensory epithelium of the mammalian inner ear. Here the primary receptor cells transform mechanical input into electrical signals that are sent to the central nervous system by the auditory nerve [1]. However, unlike vision, touch and the chemical senses, sound transduction is modulated by efferent signals (olivocochlear, OC) that travel in reverse, from the brain back to the inner ear [2]. The present work reviews the data which demonstrates that synaptic transmission between medial OC (MOC) fibers and cochlear hair cells is mediated by a peculiar nicotinic cholinergic receptor (nAChR), the α9α10 receptor. In addition, we discuss possible pharmacological targeting of this receptor in inner ear pathologies, as well as in auditory processing disorders and reading disabilities.
Section snippets
Organization of the mammalian cochlea
There are approximately 16,000 sensory hair cells in the human cochlea. They are organized in a tonotopic fashion, with those sensitive to high frequency sound at the basal end and those sensitive to low frequency at the apical end of the cochlear coil [1]. Hair cells are neuroepithelial cells, with the apical pole specialized for mechanotransduction and the basal pole specialized for the release of neurotransmitter. The mammalian cochlea contains two classes of hair cells arranged in rows
Amplification in the mammalian ear
The receptor cells of most sensory organs must amplify their signals in order to separate them from background noise. Photoreceptors, for example, use a biochemical cascade to enhance their responses several thousand-fold after transduction has been accomplished. Cochlear hair cells, instead use an active mechanical process to amplify their inputs [6], [7]. When sound reaches the cochlea, it elicits mechanical vibrations that are sensed and transduced into an electrical response by motion of
Amplification is under the control of the medial olivocochlear system
The MOC efferents (Fig. 1A) originate in the medial portion of the superior olivary complex and project to the organ of Corti, where they form large synaptic contacts with OHCs (Fig. 1A and B) [2]. Activation of the MOC pathway reduces cochlear sensitivity and tuning in a frequency selective manner, by inhibiting the mechanical amplification of low-level sounds that occurs before the sound stimulates the IHCs and the auditory nerve fibers [2], [15]. Olivocochlear efferent neurons permit the
The nicotinic cholinergic receptor of cochlear hair cells
Acetylcholine (ACh) is the principal neurotransmitter released by MOC terminals. While both muscarinic and nicotinic receptors have been proposed to mediate the effects of ACh in the cochlea, pharmacological and electrophysiological data suggest a central role for an atypical, nAChR located at the synapse between efferent fibers and OHCs [15], [26], [27], [28], [29], [30], [31], [32], [33], [34]. Current data indicates that activation of the hair cell nAChR leads to an increase in intracellular
Hearing loss
Millions of people the world round have hearing loss or associated conditions, such as tinnitus, otitis media and Ménières disease. According to the World Health Organization 250 million people worldwide have a moderate-to-severe or greater hearing loss (www.who.int/pbd/deafness/facts/en/index.html). This figures more than doubles if people with mild hearing loss are included. Hearing impairment is one of the most common sensory disabilities, and may drastically limit the quality of life, with
Targeting α9α10 nAChRs
The evidence that nAChRs play a role in a number of different neural functions and disorders has given impetus to the search for drugs that selectively affect different receptor subtypes. However, the recent findings indicating that native receptors are much more heterogeneous than previously thought [116], has hampered the development of receptor-specific compounds [117]. This difficulty is most likely overcome in the case of α9 and α10-containing nAChRs, since these subunits appear only to
Conclusions
Much has been learned over the last 60 years concerning the properties and function of the efferent system to the cochlea, beginning with its first description [4], the characterization of the effects of ACh on isolated hair cells [32], [34], to the cloning of the atypical cholinergic receptor of hair cells [37], [47]. The following years will probably witness the design of hair cell nAChR-based therapies. This most likely will include drugs to prevent NIHL, to alleviate tinnitus and to treat
Acknowledgements
ABE, EK and PAF are supported by the National Institutes of Deafness and other Communication Disorders (NIDCD) Grant R01DC001508. ABE is supported by an International Research Scholar Grant from the Howard Hughes Medical Institute, the Tinnitus Research Initiative, Research Grants from ANPCyT (Argentina) and the University of Buenos Aires (Argentina). EK is supported by Research Grants from the University of Buenos Aires (Argentina) and CONICET (Argentina).
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