Noise-induced plasticity of KCNQ2/3 and HCN channels underlies vulnerability and resilience to tinnitus

Li, Shuang; Kalappa, Bopanna I.; Tzounopoulos, Thanos

doi:10.7554/elife.07242

Cited by 63 publications

(66 citation statements)

References 81 publications

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“…Moreover, these results are consistent with reduced ABR thresholds (Fig. S4 A-D) and with previous studies showing damage of AN terminals even after milder acoustic trauma (37,38). We hypothesized that the lack of a ZX1 effect on PF EPSCs may be due to a decrease in zinc inhibition in PF EPSCs.…”

Section: Plasticity Of Ampar Epscs By Sound-evoked Reduction Of Presysupporting

confidence: 81%

AMPA receptor inhibition by synaptically released zinc

Kalappa

Anderson

Goldberg

et al. 2015

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

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109

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The vast amount of fast excitatory neurotransmission in the mammalian central nervous system is mediated by AMPA-subtype glutamate receptors (AMPARs). As a result, AMPAR-mediated synaptic transmission is implicated in nearly all aspects of brain development, function, and plasticity. Despite the central role of AMPARs in neurobiology, the fine-tuning of synaptic AMPA responses by endogenous modulators remains poorly understood. Here we provide evidence that endogenous zinc, released by single presynaptic action potentials, inhibits synaptic AMPA currents in the dorsal cochlear nucleus (DCN) and hippocampus. Exposure to loud sound reduces presynaptic zinc levels in the DCN and abolishes zinc inhibition, implicating zinc in experience-dependent AMPAR synaptic plasticity. Our results establish zinc as an activity-dependent, endogenous modulator of AMPARs that tunes fast excitatory neurotransmission and plasticity in glutamatergic synapses.AMPA receptors | zinc | ZnT3 | synaptic plasticity | auditory T he development, function, and experience-dependent plasticity of the mammalian brain depend on the refined neuronal interactions that occur in synapses. In the majority of excitatory synapses, the release of the neurotransmitter glutamate from presynaptic neurons opens transmembrane ion channels in postsynaptic neurons, the ionotropic glutamate receptors, thereby generating the flow of excitatory signaling in the brain. As a result, these receptors play a fundamental role in normal function and development of the brain, and they are also involved in many brain disorders (1).The ionotropic glutamate receptor family consists of AMPA, kainate, and NMDA receptors (NMDARs). Although kainate receptor-mediated excitatory postsynaptic responses occur in a few central synapses (2), AMPA receptors (AMPARs) and NMDARs are localized in the postsynaptic density of the vast majority of glutamatergic synapses in the brain, mediating most of excitatory neurotransmission (1). NMDAR function is regulated by a wide spectrum of endogenous allosteric neuromodulators that fine-tune synaptic responses (3-5); however, much less is known about endogenous AMPAR neuromodulators [(1, 5), but see refs. 6 and 7]. Recent structural studies revealed that the amino terminal domain (ATD) and ligand-binding domain (LBD) are tightly packed in NMDARs but not AMPARs (8-10). These structural differences explain some of the functional differences in allosteric modulation between AMPARs and NMDARs, such as why the ATD of NMDARs, unlike that of AMPARs, modulates function and contains numerous binding sites for allosteric regulators. Nonetheless, given the importance of fine-tuning both synaptic AMPAR and NMDAR responses for brain function, it is puzzling that there is not much evidence for endogenous, extracellular AMPAR modulation. The discovery and establishment of endogenous AMPAR modulators is crucial both for understanding ionotropic glutamate receptor signaling and for developing therapeutic agents for the treatment of AMPAR-related disorders, such as d...

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Section: Plasticity Of Ampar Epscs By Sound-evoked Reduction Of Presysupporting

confidence: 81%

AMPA receptor inhibition by synaptically released zinc

Kalappa

Anderson

Goldberg

et al. 2015

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

Self Cite

109

149

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“…The KCNQ family comprises five subunits (KCNQ1-5): KCNQ2-5 are confined to the nervous system, including the brainstem and inner ear, whereas KCNQ1 is limited to the heart and peripheral epithelial and smooth muscle cells (Howard et al, 2007). Genetic mutations in either KCNQ2 or KCNQ3 subunits are linked to benign familial neonatal convulsions, whereas noise-induced reduction in KCNQ2/3 channel activity leads to development of tinnitus in mice (Biervert et al, 1998;Jentsch, 2000;Li et al, 2013;Li et al, 2015). Moreover, pathologic reduction in KCNQ2/3 channel activity is involved in different classes of seizures, neuropathic pain, migraine, anxiety, attention deficient-hyperactivity disorder, schizophrenia, mania, and bipolar disease (Munro and Dalby-Brown, 2007;Hansen et al, 2008;Grunnet et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

Synthesis and Evaluation of Potent KCNQ2/3-Specific Channel Activators

et al. 2016

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KQT-like subfamily (KCNQ) channels are voltage-gated, noninactivating potassium ion channels, and their down-regulation has been implicated in several hyperexcitability-related disorders, including epilepsy, neuropathic pain, and tinnitus. Activators of these channels reduce the excitability of central and peripheral neurons, and, as such, have therapeutic utility. Here, we synthetically modified several moieties of the KCNQ2-5 channel activator retigabine, an anticonvulsant approved by the U.S. Food and Drug Administration. By introducing a CF 3 -group at the 4-position of the benzylamine moiety, combined with a fluorine atom at the 3-position of the aniline ring, we generated Ethyl (2-amino-3-fluoro-4-((4-(trifluoromethyl)benzyl)amino)phenyl)carbamate (RL648_81), a new KCNQ2/3-specific activator that is .15 times more potent and also more selective than retigabine. We suggest that RL648_81 is a promising clinical candidate for treating or preventing neurologic disorders associated with neuronal hyperexcitability.

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“…[5] This hyperactivity is caused, at least in part, by decreased Kv7.2/3 (KCNQ2/3) potassium currents. [6] However, only those mice with an ongoing Kv7.2/3 activity reduction develop tinnitus, whereas mice that are able to reestablish Kv7.2/3 channel activity are resistant to tinnitus. [6] 2.1.…”

Section: Kv7 (Kcnq) Potassium Channelsmentioning

confidence: 99%

“…[6] However, only those mice with an ongoing Kv7.2/3 activity reduction develop tinnitus, whereas mice that are able to reestablish Kv7.2/3 channel activity are resistant to tinnitus. [6] 2.1. Pharmacological modulation of Kv7 potassium channels and tinnitus…”

Section: Kv7 (Kcnq) Potassium Channelsmentioning

confidence: 99%