Harmonin inhibits presynaptic Cav1.3 Ca2+ channels in mouse inner hair cells

Gregory, Frederick D.; Bryan, Keith E.; Pangršič, Tina; Calin‐Jageman, Irina; Moser, Tobias; Lee, Amy

doi:10.1038/nn.2895

Cited by 84 publications

(144 citation statements)

References 15 publications

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“…Consistent with these results, IHCs lacking harmonin in dfcr mice also have greater Ca 2+ currents, with a negative shift in voltage-dependence, and a clustering defect of Ca V 1.3 Ca 2+ channels (27,28). Based on the observed interactions of clarin-1 ( Figure 11E), we suggest that clarin-1, harmonin, and Ca V 1.3 channels, via their Ca 2+ channel subunit Ca V β 2 , form a molecular platform associated with F-actin in the active zones of the IHC.…”

Section: Hearing Rescue By Virus-mediated Gene Transfer Into the Ihcssupporting

confidence: 72%

“…Could the postsynaptic defects observed in Clrn1 ex4fl/fl Myo15-Cre +/-mice result purely from disorganization of the presynaptic Ca V 1.3 complex? This seems unlikely, because an absence of the presynaptic cytomatrix protein bassoon (36), Ca V β 2 (37), or harmonin (27,28) in IHCs disorganizes the Ca V 1.3 channels without affecting the postsynaptic clustering of glutamate receptors. As an alternative hypothesis, clarin-1 may be a member of pre-and postsynaptic membrane focal adhesion complexes at the IHC ribbon synapse, possibly interacting with proteins known to be involved in the extracellular matrix at neuronal synapses, such as thrombospondins (38), or in membrane-membrane synaptic adhesion, such as Eph/ephrins, cadherins, and the neurexin the Rosenthal's canals of control, Clrn1 ex4-/-, and Clrn1 ex4fl/fl Myo15-Cre +/-mice on P24-P30 ( Figure 12E).…”

Section: Hearing Rescue By Virus-mediated Gene Transfer Into the Ihcsmentioning

confidence: 99%

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Clarin-1 gene transfer rescues auditory synaptopathy in model of Usher syndrome

Dulon¹,

Papal²,

Patni³

et al. 2018

Journal of Clinical Investigation

110

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Section: Hearing Rescue By Virus-mediated Gene Transfer Into the Ihcssupporting

confidence: 72%

Section: Hearing Rescue By Virus-mediated Gene Transfer Into the Ihcsmentioning

confidence: 99%

Clarin-1 gene transfer rescues auditory synaptopathy in model of Usher syndrome

Dulon¹,

Papal²,

Patni³

et al. 2018

Journal of Clinical Investigation

110

View full text Add to dashboard Cite

“…The Ca 2+ -channel complex at IHC AZs is likely composed of splice variants of the pore-forming subunit Ca V 1.3α containing exons 43S or 43L (36), of the Ca V β2 (33), and less likely of other Ca V β subunits (32), and of a yet-to-be-identified Ca V α2δ subunit. Ca V β2, the synaptic ribbon, and the presynaptic scaffolds bassoon and RIM2α and β were previously shown to promote the abundance of Ca V 1.3 at IHC AZs (15,33,43), whereas harmonin seems to reduce the number of synaptic Ca V 1.3 (44). Work in zebrafish hair cells has revealed an intriguing molecular interplay between RIBEYE and Ca V 1.3 channels, whereby RIBEYE overexpression promotes the formation of Ca V 1.3-positive AZ-like specializations and synaptic Ca 2+ influx negatively regulates RIBEYE abundance at the AZ (63,64).…”

Section: Discussionmentioning

confidence: 98%

“…5H), and normal sound-pressure dependence of firing (Fig. 5I) (44,45). Here, we revisited the regulation of IHC AZs by harmonin in deaf-circler mice (dfcr) (46), reasoning that site-specific expression of harmonin might contribute to the heterogeneity of maximal Ca 2+ influx and voltage dependence of activation.…”

Section: Significancementioning

confidence: 92%

Hair cells use active zones with different voltage dependence of Ca ²⁺ influx to decompose sounds into complementary neural codes

Ohn

Rutherford

Jing

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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For sounds of a given frequency, spiral ganglion neurons (SGNs) with different thresholds and dynamic ranges collectively encode the wide range of audible sound pressures. Heterogeneity of synapses between inner hair cells (IHCs) and SGNs is an attractive candidate mechanism for generating complementary neural codes covering the entire dynamic range. Here, we quantified active zone (AZ) properties as a function of AZ position within mouse IHCs by combining patch clamp and imaging of presynaptic Ca 2+ influx and by immunohistochemistry. We report substantial AZ heterogeneity whereby the voltage of half-maximal activation of Ca 2+ influx ranged over ∼20 mV. Ca 2+ influx at AZs facing away from the ganglion activated at weaker depolarizations. Estimates of AZ size and Ca 2+ channel number were correlated and larger when AZs faced the ganglion. Disruption of the deafness gene GIPC3 in mice shifted the activation of presynaptic Ca 2+ influx to more hyperpolarized potentials and increased the spontaneous SGN discharge. Moreover, Gipc3 disruption enhanced Ca 2+ influx and exocytosis in IHCs, reversed the spatial gradient of maximal Ca 2+ influx in IHCs, and increased the maximal firing rate of SGNs at sound onset. We propose that IHCs diversify Ca 2+ channel properties among AZs and thereby contribute to decomposing auditory information into complementary representations in SGNs.auditory system | spiral ganglion neuron | dynamic range | synaptic strength | presynaptic heterogeneity T he auditory system enables us to perceive sound pressures that vary over six orders of magnitude. This is achieved by active amplification of cochlear vibrations at low sound pressures and compression at high sound pressures. The receptor potential of inner hair cells (IHCs) represents the full range (1), whereas each postsynaptic type I spiral ganglion neuron (hereafter termed SGN) encodes only a fraction (2-6). SGNs with comparable frequency tuning but different spontaneous spike rates and sound responses are thought to emanate from neighboring, if not the same, IHC at a given tonotopic position of the organ of Corti (2,5,7,8). Even in silence, IHC active zones (AZs) release glutamate at varying rates, evoking "spontaneous" spiking in SGNs. SGNs with greater spontaneous spike rates respond to softer sounds (highspontaneous rate, low-threshold SGNs), than those with lower spontaneous spike rates (low-spontaneous rate, high-threshold SGNs) (2, 9). This diversity likely underlies the representation of sounds across all audible sound pressure levels in the auditory nerve, to which neural adaptation also contributes (10).How SGN diversity arises is poorly understood. Candidate mechanisms include the heterogeneity of ribbon synapses that differ in pre-and/or postsynaptic properties even within individual IHCs (7,(11)(12)(13)(14). IHC AZs vary in the number (11, 15) and voltage dependence of gating (11) of their Ca 2+ channels regardless of tonotopic position (16). Lateral olivocochlear efferent projections to the SGNs regulate postsynaptic exc...

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“…1). In this minireview, we limit our focus to the roles of USH proteins in the hair cell stereocilia, even though some of these proteins are also important for signal transmission at the hair cell synapses (13,14).…”

mentioning

confidence: 99%