Age-related hearing loss pertaining to potassium ion channels in the cochlea and auditory pathway

Abstract

Age-related hearing loss (ARHL) is the most prevalent sensory deficit in the elderly and constitutes the third highest risk factor for dementia. Lifetime noise exposure, genetic predispositions for degeneration, and metabolic stress are assumed to be the major causes of ARHL. Both noise-induced and hereditary progressive hearing have been linked to decreased cell surface expression and impaired conductance of the potassium ion channel K_V7.4 (KCNQ4) in outer hair cells, inspiring future therapies to maintain or prevent the decline of potassium ion channel surface expression to reduce ARHL. In concert with K_V7.4 in outer hair cells, K_V7.1 (KCNQ1) in the stria vascularis, calcium-activated potassium channels BK (KCNMA1) and SK2 (KCNN2) in hair cells and efferent fiber synapses, and K_V3.1 (KCNC1) in the spiral ganglia and ascending auditory circuits share an upregulated expression or subcellular targeting during final differentiation at hearing onset. They also share a distinctive fragility for noise exposure and age-dependent shortfalls in energy supply required for sustained surface expression. Here, we review and discuss the possible contribution of select potassium ion channels in the cochlea and auditory pathway to ARHL. We postulate genes, proteins, or modulators that contribute to sustained ion currents or proper surface expressions of potassium channels under challenging conditions as key for future therapies of ARHL.

Keywords: BK; Kv3.1; Kv7.1; Kv7.4; Presbycusis; SK2.

Fig. 1

K⁺ expression along the ascending auditory pathway before and after hearing onset. a Before the onset of hearing, potassium ion (K⁺) channels are mainly expressed in the organ of Corti. In the outer hair cells (OHC), K_V7.4 (KCNQ4, green) is found along the entire basolateral membrane, while the inner hair cells (IHCs) express the calcium-activated potassium channel SK2 (KCNN2, purple) before postnatal day (P) 12 in mice, corresponding to embryonic week (EW) 27 in humans. For reference, afferent (gray) and efferent (black) neural projections are shown. b In the mature organ of Corti, the endolymph of the scala media contains a high concentration of K⁺, which is mediated by K_V7.1 (KCNQ1, orange) channels in the apical marginal cells of the stria vascularis (SV). During auditory stimulation, endolymphatic K⁺ enter the OHC at the basolateral membrane, and leave the cell via K_V7.4, BK (KCNMA1, blue), and SK2 channels. In the IHC, K⁺ exits the cell through K_V7.4 and BK channels. The expression of BK channels was identified at the lateral wall of IHC as well as in the cell bodies of spiral ganglion neurons (SGNs). The auditory signal is then transmitted from the cochlea to the cochlear nucleus (CN) via rapidly firing neurons containing K_V3.1 (KCNC1, red arrows) channels. From here, parvalbumin-positive interneurons project onto the lateral and medial superior olive (LSO and MSO, respectively) and the medial nucleus of the trapezoid body (MNTB), whose fibers also express K_V3.1. The inferior colliculus (IC) receives input from the contralateral (not shown) and ipsilateral superior olivary complex. The fibers from the IC project to the medial genicular body (MGB) and the signals are then transmitted to the auditory cortex (AC) via rapid firing, K_V3.1 expressing neurons

Fig. 2

a In the challenged auditory system leading to age-related hearing loss (ARHL), the key causing factors are postulated to be lifetime noise exposure, hereditary predisposition, and the accumulation of reactive oxygen species (ROS). b In a healthy outer hair cell (OHC), potassium ions (K⁺) enter the cell through apical mechanosensitive channels and are then transported to the supporting cells through K_V7.4 (KCNQ4, green) channels on the basolateral membrane of OHC. However, in the challenged system, the expression of K_V7.4 is reduced, resulting in a poor K⁺ efflux. This state can be influenced by the addition of K⁺ channel modulators (green circle) in a way where cell surface expression remains stable but the efflux rate can be increased. c In fast-spiking, parvalbumin-positive interneurons, K_V3.1 (KCNC1, red) is required for the high-frequency repetitive firing. A decline in K_V3.1 cell surface expression leads to an incapacity of neurons to maintain high-frequency firing action potentials. Modulators that bind to K_V3.1 (red circle) may lower action potential latencies and duration and increase the firing pattern of these neurons