Down-regulation of Cav1.3 in auditory pathway promotes age-related hearing loss by enhancing calcium-mediated oxidative stress in male mice

Fan, Qi; Zhang, Rongsheng; Chen, Jin; Zhao, Fei; Sun, Yanbo; Du, Zhenhua; Dai, Bing; Li, Pengjun; Zhu, Hongmei; Chu, Hanqi

doi:10.18632/aging.102203

Cited by 14 publications

(8 citation statements)

References 33 publications

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“…Nifedipine can block Cav1.2 current [ 146 ] Oxidative stress pathway for affective disorders [ 156 ] Apoptotic pathway in Timothy syndrome [ 153 ] Apoptotic pathway in dilated cardiomyopathy [ 154 ] CACNA1D Calcium voltage-gated channel subunit alpha1 D Cav1.3 L-type None Zebrafish larvae for schizophrenia [ 251 ]. Animal model of epilepsy [ 252 ] None Oxidative stress pathway in hearing loss [ 157 ] CACNA1E Calcium voltage-gated channel subunit alpha1 E Cav2.3 R-type Mouse model of Fragile X Syndrome [ 253 ] Sprague–Dawley rats for epilepsy [ 254 ]. Cancer pain mouse model [ 255 ].…”

Section: Resultsmentioning

confidence: 99%

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Calcium channelopathies and intellectual disability: a systematic review

Kessi

Chen

Peng

et al. 2021

Orphanet J Rare Dis

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Background Calcium ions are involved in several human cellular processes including corticogenesis, transcription, and synaptogenesis. Nevertheless, the relationship between calcium channelopathies (CCs) and intellectual disability (ID)/global developmental delay (GDD) has been poorly investigated. We hypothesised that CCs play a major role in the development of ID/GDD and that both gain- and loss-of-function variants of calcium channel genes can induce ID/GDD. As a result, we performed a systematic review to investigate the contribution of CCs, potential mechanisms underlying their involvement in ID/GDD, advancements in cell and animal models, treatments, brain anomalies in patients with CCs, and the existing gaps in the knowledge. We performed a systematic search in PubMed, Embase, ClinVar, OMIM, ClinGen, Gene Reviews, DECIPHER and LOVD databases to search for articles/records published before March 2021. The following search strategies were employed: ID and calcium channel, mental retardation and calcium channel, GDD and calcium channel, developmental delay and calcium channel. Main body A total of 59 reports describing 159 cases were found in PubMed, Embase, ClinVar, and LOVD databases. Variations in ten calcium channel genes including CACNA1A, CACNA1C, CACNA1I, CACNA1H, CACNA1D, CACNA2D1, CACNA2D2, CACNA1E, CACNA1F, and CACNA1G were found to be associated with ID/GDD. Most variants exhibited gain-of-function effect. Severe to profound ID/GDD was observed more for the cases with gain-of-function variants as compared to those with loss-of-function. CACNA1E, CACNA1G, CACNA1F, CACNA2D2 and CACNA1A associated with more severe phenotype. Furthermore, 157 copy number variations (CNVs) spanning calcium genes were identified in DECIPHER database. The leading genes included CACNA1C, CACNA1A, and CACNA1E. Overall, the underlying mechanisms included gain- and/ or loss-of-function, alteration in kinetics (activation, inactivation) and dominant-negative effects of truncated forms of alpha1 subunits. Forty of the identified cases featured cerebellar atrophy. We identified only a few cell and animal studies that focused on the mechanisms of ID/GDD in relation to CCs. There is a scarcity of studies on treatment options for ID/GDD both in vivo and in vitro. Conclusion Our results suggest that CCs play a major role in ID/GDD. While both gain- and loss-of-function variants are associated with ID/GDD, the mechanisms underlying their involvement need further scrutiny.

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Section: Resultsmentioning

confidence: 99%

“…Gabapentin is a ligand of Cav1.3 [ 151 ]. The commonest affected pathway for the available studies is the apoptotic pathway [ 152 – 155 ] followed by oxidative stress pathway [ 156 , 157 ] and autophagy [ 158 ]. More details can be found in Table 2 .…”

Section: Summary Of the Clinical Featuresmentioning

confidence: 99%

Calcium channelopathies and intellectual disability: a systematic review

Kessi

Chen

Peng

et al. 2021

Orphanet J Rare Dis

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“…Severe to profound hearing loss is a common finding in these patients. These ion channels seem to also play a role in calcium-mediated oxidative stress leading to age-related hearing loss in male mice [67] and in inner ear differentiation [68].…”

Section: Presynaptic Synaptopathiesmentioning

confidence: 99%

Auditory Neuropathy Spectrum Disorders: From Diagnosis to Treatment: Literature Review and Case Reports

Siati

Rosenzweig

Gersdorff

et al. 2020

JCM

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Auditory neuropathy spectrum disorder (ANSD) refers to a range of hearing impairments characterized by deteriorated speech perception, despite relatively preserved pure-tone detection thresholds. Affected individuals usually present with abnormal auditory brainstem responses (ABRs), but normal otoacoustic emissions (OAEs). These electrophysiological characteristics have led to the hypothesis that ANSD may be caused by various dysfunctions at the cochlear inner hair cell (IHC) and spiral ganglion neuron (SGN) levels, while the activity of outer hair cells (OHCs) is preserved, resulting in discrepancies between pure-tone and speech comprehension thresholds. The exact prevalence of ANSD remains unknown; clinical findings show a large variability among subjects with hearing impairment ranging from mild to profound hearing loss. A wide range of prenatal and postnatal etiologies have been proposed. The study of genetics and of the implicated sites of lesion correlated with clinical findings have also led to a better understanding of the molecular mechanisms underlying the various forms of ANSD, and may guide clinicians in better screening, assessment and treatment of ANSD patients. Besides OAEs and ABRs, audiological assessment includes stapedial reflex measurements, supraliminal psychoacoustic tests, electrocochleography (ECochG), auditory steady-state responses (ASSRs) and cortical auditory evoked potentials (CAEPs). Hearing aids are indicated in the treatment of ANSD with mild to moderate hearing loss, whereas cochlear implantation is the first choice of treatment in case of profound hearing loss, especially in case of IHC presynaptic disorders, or in case of poor auditory outcomes with conventional hearing aids.

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“…The Cav1.3 channels are ideal calcium channels for mediating rapid and continuous exocytosis, as they can be activated by lower voltages than those needed to activate other Cav1 channels [ 32 ]. Cav1.3 channels cluster tightly at synaptic ribbons and are important for tightly coupled calcium influx and vesicle release [ 59 ].…”

Section: Mechanisms Of Ribbon Synapse Damagementioning

confidence: 99%

Protection of Cochlear Ribbon Synapses and Prevention of Hidden Hearing Loss

et al. 2020

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In the auditory system, ribbon synapses are vesicle-associated structures located between inner hair cells (IHCs) and spiral ganglion neurons that are implicated in the modulation of trafficking and fusion of synaptic vesicles at the presynaptic terminals. Synapse loss may result in hearing loss and difficulties with understanding speech in a noisy environment. This phenomenon happens without permanent hearing loss; that is, the cochlear synaptopathy is “hidden.” Recent studies have reported that synapse loss might be critical in the pathogenesis of hidden hearing loss. A better understanding of the molecular mechanisms of the formation, structure, regeneration, and protection of ribbon synapses will assist in the design of potential therapeutic strategies. In this review, we describe and summarize the following aspects of ribbon synapses: (1) functional and structural features, (2) potential mechanisms of damage, (3) therapeutic research on protecting the synapses, and (4) the role of synaptic regeneration in auditory neuropathy and the current options for synapse rehabilitation.

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Down-regulation of Cav1.3 in auditory pathway promotes age-related hearing loss by enhancing calcium-mediated oxidative stress in male mice

Cited by 14 publications

References 33 publications

Calcium channelopathies and intellectual disability: a systematic review

Calcium channelopathies and intellectual disability: a systematic review

Auditory Neuropathy Spectrum Disorders: From Diagnosis to Treatment: Literature Review and Case Reports

Protection of Cochlear Ribbon Synapses and Prevention of Hidden Hearing Loss

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