Ca_V1.3 Channels Are Essential for Development and Presynaptic Activity of Cochlear Inner Hair Cells

Abstract

Cochlear inner hair cells (IHCs) release neurotransmitter onto afferent auditory nerve fibers in response to sound stimulation. During early development, afferent synaptic transmission is triggered by spontaneous Ca2+ spikes of IHCs, which are under efferent cholinergic control. Around the onset of hearing, large-conductance Ca2+-activated K+ channels are acquired, and Ca2+ spikes as well as the cholinergic innervation are lost. Here, we performed patch-clamp measurements in IHCs of mice lacking the CaV1.3 channel (CaV1.3-/-) to investigate the role of this prevailing voltage-gated Ca2+ channel in IHC development and synaptic function. The small Ca2+ current remaining in IHCs from 3-week-old CaV1.3-/- mice was mainly mediated by L-type Ca2+ channels, because it was sensitive to dihydropyridines but resistant to inhibitors of non-L-type Ca2+ channels such as omega-conotoxins GVIA and MVIIC and SNX-482. Depolarization induced only marginal exocytosis in CaV1.3-/- IHC, which was solely mediated by L-type Ca2+ channels, whereas robust exocytic responses were elicited by photolysis of caged Ca2+. Secretion triggered by short depolarizations was reduced proportionally to the Ca2+ current, suggesting that the coupling of the remaining channels to exocytosis was unchanged. CaV1.3-/- IHCs lacked the Ca2+ action potentials and displayed a complex developmental failure. Most strikingly, we observed a continued presence of efferent cholinergic synaptic transmission and a lack of functional large-conductance Ca2+-activated K+ channels up to 4 weeks after birth. We conclude that CaV1.3 channels are essential for normal hair cell development and synaptic transmission.

The human L-type calcium channel Cav1.3 regulates insulin release and polymorphisms in CACNA1D associate with type 2 diabetes

“…Considering that the neuroendocrine beta cell also fires action potentials in the physiological resting (or preprandial) condition [43], Ca v 1.3, with its low activation threshold, might be a good candidate for these events. In the glutamate-releasing inner-ear hair cell, Ca v 1.3 has been shown to be responsible for the generation of spontaneous action potentials, important for the maturation of synaptic connections within the developing cochlea [44]. In a remarkable analogy, the postnatal maturation of mouse beta cells has also been suggested to be dependent on the presence of Ca v 1.3 [8], although spontaneous spiking during this process has never been investigated.…”

CaV1.3 as pacemaker channels in adrenal chromaffin cells: Specific role on exo- and endocytosis?

“…20,[22][23][24][25][26][27] Fourth, Ca V 1.3 channels activate at very low voltages and inactivate slowly with respect to Ca V 1.2 and other high-threshold channels (N, P/Q, R). 2,28,29 This enables Ca V 1.3 to carry pacemaker currents sustaining chromaffin cell spontaneous activity. 6,15,20 Finally, Ca V 1.3 is tightly coupled to fast inactivating BK channels, suggesting a key control of AP firings and shape.…”

Cochlear Function in Mice Lacking the BK Channel α, β1, or β4 Subunits

“…Because mice with hearing deficits arising from the genetic deletion of ion channels can show hair cell degeneration (32)(33)(34) or otherwise abnormal innervation (35), organs of Corti excised from 8-week-old Slo ϩ/ϩ and Slo Ϫ/Ϫ mice were immunostained to assess the morphology and synaptic architecture of the IHCs (Fig. 2).…”