Burst activity and ultrafast activation kinetics of CaV1.3 Ca2+ channels support presynaptic activity in adult gerbil hair cell ribbon synapses

Zampini, Valeria; Johnson, Stuart L.; Franz, Christoph; Knipper, Marlies; Holley, Matthew C.; Magistretti, Jacopo; Masetto, Sergio; Marcotti, Walter

doi:10.1113/jphysiol.2013.251272

Cited by 47 publications

(118 citation statements)

References 38 publications

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“…Animals of either sex were killed by cervical dislocation, under Schedule 1 in accordance with UK Home Office regulations and approved by the University of Sheffield Ethical Review Committee. Cochleae were dissected as described (23,39). Whole-cell patch-clamp recordings were performed at room temperature (22-24°C).…”

Section: Methodsmentioning

confidence: 99%

Calcium entry into stereocilia drives adaptation of the mechanoelectrical transducer current of mammalian cochlear hair cells

Corns

Johnson

Kros

et al. 2014

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

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105

185

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Mechanotransduction in the auditory and vestibular systems depends on mechanosensitive ion channels in the stereociliary bundles that project from the apical surface of the sensory hair cells. In lower vertebrates, when the mechanoelectrical transducer (MET) channels are opened by movement of the bundle in the excitatory direction, Ca 2+ entry through the open MET channels causes adaptation, rapidly reducing their open probability and resetting their operating range. It remains uncertain whether such Ca 2+ -dependent adaptation is also present in mammalian hair cells. Hair bundles of both outer and inner hair cells from mice were deflected by using sinewave or step mechanical stimuli applied using a piezo-driven fluid jet. We found that when cochlear hair cells were depolarized near the Ca 2+ reversal potential or their hair bundles were exposed to the in vivo endolymphatic Ca 2+ concentration (40 μM), all manifestations of adaptation, including the rapid decline of the MET current and the reduction of the available resting MET current, were abolished. MET channel adaptation was also reduced or removed when the intracellular Ca 2+ buffer 1,2-Bis(2-aminophenoxy)ethane-N,N,N′,N′-tetraacetic acid (BAPTA) was increased from a concentration of 0.1 to 10 mM. The findings show that MET current adaptation in mouse auditory hair cells is modulated similarly by extracellular Ca 2+ , intracellular Ca 2+ buffering, and membrane potential, by their common effect on intracellular free Ca 2+ .H earing and balance depend on the transduction of mechanical stimuli into electrical signals. This process depends on the opening of mechanoelectrical transducer (MET) channels located at the tips of the shorter of pairs of adjacent stereocilia (1), which are specialized microvilli-like structures that form the hair bundles that project from the upper surface of hair cells (2,3). Deflection of hair bundles in the excitatory direction (i.e., toward the taller stereocilia) stretches specialized linkages, the tip-links, present between adjacent stereocilia (3-5), opening the MET channels. In hair cells from lower vertebrates, open MET channels reclose during constant stimuli via an initial fast adaptation mechanism followed by a much slower, myosin-based motor process, both of which are driven by Ca 2+ entry through the channel itself (6-13). In mammalian auditory hair cells, MET current adaptation seems to be mainly driven by the fast mechanism (14-16), although the exact process by which it occurs is still largely unknown. The submillisecond speed associated with the adaptation kinetics of the MET channels in rat and mouse cochlear hair cells (17,18) indicates that Ca 2+ , to cause adaptation, has to interact directly with a binding site on the channel or via an accessory protein (16). However, a recent investigation on rat auditory hair cells has challenged the view that Ca 2+ entry is required for fast adaptation, and instead proposed an as-yetundefined mechanism involving a Ca 2+ -independent reduction in the viscoelastic force of ele...

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Section: Methodsmentioning

confidence: 99%

Calcium entry into stereocilia drives adaptation of the mechanoelectrical transducer current of mammalian cochlear hair cells

Corns

Johnson

Kros

et al. 2014

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

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105

185

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“…Rab3-interacting molecule | active zone | ribbon synapse | Ca 2+ channel | vesicle T ens of Ca V 1.3 Ca 2+ channels are thought to cluster within the active zone (AZ) membrane underneath the presynaptic density of inner hair cells (IHCs) (1)(2)(3)(4). They make up the key signaling element, coupling the sound-driven receptor potential to vesicular glutamate release (5)(6)(7).…”

Section: Camentioning

confidence: 99%

Rab3-interacting molecules 2α and 2β promote the abundance of voltage-gated Ca _V 1.3 Ca ²⁺ channels at hair cell active zones

Jung

Oshima-Takago

Chakrabarti

et al. 2015

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

163

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Ca2+ influx triggers the fusion of synaptic vesicles at the presynaptic active zone (AZ). Here we demonstrate a role of Ras-related in brain 3 (Rab3)-interacting molecules 2α and β (RIM2α and RIM2β) in clustering voltage-gated Ca V 1.3 Ca 2+ channels at the AZs of sensory inner hair cells (IHCs). We show that IHCs of hearing mice express mainly RIM2α, but also RIM2β and RIM3γ, which all localize to the AZs, as shown by immunofluorescence microscopy. Immunohistochemistry, patch-clamp, fluctuation analysis, and confocal Ca 2+ imaging demonstrate that AZs of RIM2α-deficient IHCs cluster fewer synaptic Ca V 1.3 Ca 2+ channels, resulting in reduced synaptic Ca 2+ influx. Using superresolution microscopy, we found that Ca 2+ channels remained clustered in stripes underneath anchored ribbons. Electron tomography of high-pressure frozen synapses revealed a reduced fraction of membrane-tethered vesicles, whereas the total number of membrane-proximal vesicles was unaltered. Membrane capacitance measurements revealed a reduction of exocytosis largely in proportion with the Ca 2+ current, whereas the apparent Ca 2+ dependence of exocytosis was unchanged. Hair cell-specific deletion of all RIM2 isoforms caused a stronger reduction of Ca 2+ influx and exocytosis and significantly impaired the encoding of sound onset in the postsynaptic spiral ganglion neurons. Auditory brainstem responses indicated a mild hearing impairment on hair cell-specific deletion of all RIM2 isoforms or global inactivation of RIM2α. We conclude that RIM2α and RIM2β promote a large complement of synaptic Ca 2+ channels at IHC AZs and are required for normal hearing.ens of Ca V 1.3 Ca 2+ channels are thought to cluster within the active zone (AZ) membrane underneath the presynaptic density of inner hair cells (IHCs) (1-4). They make up the key signaling element, coupling the sound-driven receptor potential to vesicular glutamate release (5-7). The mechanisms governing the number of Ca 2+ channels at the AZ as well as their spatial organization relative to membrane-tethered vesicles are not well understood. Disrupting the presynaptic scaffold protein Bassoon diminishes the numbers of Ca 2+ channels and membrane-tethered vesicles at the AZ (2, 8). However, the loss of Bassoon is accompanied by the loss of the entire synaptic ribbon, which makes it challenging to distinguish the direct effects of gene disruption from secondary effects (9).Among the constituents of the cytomatrix of the AZ, RIM1 and RIM2 proteins are prime candidates for the regulation of Ca 2+ channel clustering and function (10, 11). The family of RIM proteins has seven identified members (RIM1α, RIM1β, RIM2α, RIM2β, RIM2γ, RIM3γ, and RIM4γ) encoded by four genes (RIM1-RIM4). All isoforms contain a C-terminal C 2 domain but differ in the presence of additional domains. RIM1 and RIM2 interact with Ca 2+ channels, most other proteins of the cytomatrix of the AZ, and synaptic vesicle proteins. They interact directly with the auxiliary β (Ca V β) subunits (12, 13) and poreforming Ca V α subun...

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“…First, Ca v 1.3 activates rapidly compared to the related Ca v 1.2 channel abundant in the brain and heart [11, 12]. Whole-cell and single-channel recordings of Ca 2+ currents in IHCs indicate time constants for activation and latency to first opening in the submillisecond range [13-17]. Rapid activation kinetics of Ca v 1.3 channels are likely important for temporal aspects of sound coding, such as the rapid onset of sound and the ability to accurately trigger firing of the auditory nerve to reflect sound frequency (i.e., phase locking).…”

Section: Cav13 Channels and Hearingmentioning

confidence: 99%

Voltage-Gated Cav1 Channels in Disorders of Vision and Hearing

Joiner¹,

Lee

2015

CMP

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Cav1 channels mediate L-type Ca2+ currents that trigger the exocytotic release of glutamate from the specialized “ribbon” synapse of retinal photoreceptors (PRs) and cochlear inner hair cells (IHCs). Genetic evidence from animal models and humans support a role for Cav1.3 and Cav1.4 as the primary Cav channels in IHCs and PRs, respectively. Because of the unique features of transmission at ribbon synapses, Cav1.3 and Cav1.4 exhibit unusual properties that are well-suited for their physiological roles. These properties may be intrinsic to the channel subunit(s) and/or may be conferred by regulatory interactions with synaptic signaling molecules. This review will cover advances in our understanding of the function of Cav1 channels at sensory ribbon synapses, and how dysregulation of these channels leads to disorders of vision and hearing.

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Burst activity and ultrafast activation kinetics of Ca_V1.3 Ca²⁺ channels support presynaptic activity in adult gerbil hair cell ribbon synapses

Cited by 47 publications

References 38 publications

Calcium entry into stereocilia drives adaptation of the mechanoelectrical transducer current of mammalian cochlear hair cells

Calcium entry into stereocilia drives adaptation of the mechanoelectrical transducer current of mammalian cochlear hair cells

Rab3-interacting molecules 2α and 2β promote the abundance of voltage-gated Ca _V 1.3 Ca ²⁺ channels at hair cell active zones

Voltage-Gated Ca<sub>v</sub>1 Channels in Disorders of Vision and Hearing

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Burst activity and ultrafast activation kinetics of CaV1.3 Ca2+ channels support presynaptic activity in adult gerbil hair cell ribbon synapses

Cited by 47 publications

References 38 publications

Calcium entry into stereocilia drives adaptation of the mechanoelectrical transducer current of mammalian cochlear hair cells

Calcium entry into stereocilia drives adaptation of the mechanoelectrical transducer current of mammalian cochlear hair cells

Rab3-interacting molecules 2α and 2β promote the abundance of voltage-gated Ca V 1.3 Ca 2+ channels at hair cell active zones

Voltage-Gated Ca<sub>v</sub>1 Channels in Disorders of Vision and Hearing

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Burst activity and ultrafast activation kinetics of Ca_V1.3 Ca²⁺ channels support presynaptic activity in adult gerbil hair cell ribbon synapses

Rab3-interacting molecules 2α and 2β promote the abundance of voltage-gated Ca _V 1.3 Ca ²⁺ channels at hair cell active zones