title: α2δ2 Controls the Function and Trans-Synaptic Coupling of Cav1.3 Channels in Mouse Inner Hair Cells and Is Essential for Normal Hearing.
abstract: The auxiliary subunit α2δ2 modulates the abundance and function of voltage-gated calcium channels. Here we show that α2δ2 mRNA is expressed in neonatal and mature hair cells. A functional α2δ2-null mouse, the ducky mouse (du), showed elevated auditory brainstem response click and frequency-dependent hearing thresholds. Otoacoustic emissions were not impaired pointing to normal outer hair cell function. Peak Ca2+and Ba2+currents of mature du/du inner hair cells (IHCs) were reduced by 30-40%, respectively, and gating properties, such as the voltage of half-maximum activation and voltage sensitivity, were altered, indicating that Cav1.3 channels normally coassemble with α2δ2 at IHC presynapses. The reduction of depolarization-evoked exocytosis in du/du IHCs reflected their reduced Ca2+currents. Ca2+- and voltage-dependent K+(BK) currents and the expression of the pore-forming BKα protein were normal. Cav1.3 and Cavβ2 protein expression was unchanged in du/du IHCs, forming clusters at presynaptic ribbons. However, the close apposition of presynaptic Cav1.3 clusters with postsynaptic glutamate receptor GluA4 and PSD-95 clusters was significantly impaired in du/du mice. This implies that, in addition to controlling the expression and gating properties of Cav1.3 channels, the largely extracellularly localized α2δ2 subunit moreover plays a so far unknown role in mediating trans-synaptic alignment of presynaptic Ca2+channels and postsynaptic AMPA receptors.
  
  
  
  Inner hair cells possess calcium channels that are essential for transmitting sound information into synaptic transmitter release. Voltage-gated calcium channels can coassemble with auxiliary subunit α2δ isoforms 1-4. We found that hair cells of the mouse express the auxiliary subunit α2δ2, which is needed for normal hearing thresholds. Using a mouse model with a mutant, nonfunctional α2δ2 protein, we showed that the α2δ2 protein is necessary for normal calcium currents and exocytosis in inner hair cells. Unexpectedly, the α2δ2 protein is moreover required for the optimal spatial alignment of presynaptic calcium channels and postsynaptic glutamate receptor proteins across the synaptic cleft. This suggests that α2δ2 plays a novel role in organizing the synapse.
authors: Department of Biophysics, Center for Integrative Physiology and Molecular Medicine (CIPMM), and.
authors: Barbara
authors: B
authors: Fell
authors: Department of Biophysics, Center for Integrative Physiology and Molecular Medicine (CIPMM), and.
authors: Stephanie
authors: S
authors: Eckrich
authors: Department of Biophysics, Center for Integrative Physiology and Molecular Medicine (CIPMM), and.
authors: Kerstin
authors: K
authors: Blum
authors: Department of Biophysics, Center for Integrative Physiology and Molecular Medicine (CIPMM), and.
authors: Tobias
authors: T
authors: Eckrich
authors: Departments of Otorhinolaryngology and.
authors: Dietmar
authors: D
authors: Hecker
authors: Medical University Innsbruck, Division of Physiology, 6020 Innsbruck, Austria.
authors: Gerald J
authors: GJ
authors: Obermair
authors: Department of Biophysics, Center for Integrative Physiology and Molecular Medicine (CIPMM), and.
authors: Stefan
authors: S
authors: Münkner
authors: Experimental and Clinical Pharmacology and Toxicology, School of Medicine, Saarland University, 66421 Homburg, Germany, and.
authors: Veit
authors: V
authors: Flockerzi
authors: Departments of Otorhinolaryngology and.
authors: Bernhard
authors: B
authors: Schick
authors: Department of Biophysics, Center for Integrative Physiology and Molecular Medicine (CIPMM), and jutta.engel@uni-saarland.de.
authors: Jutta
authors: J
authors: Engel
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D015220:Calcium Channels / Q000235:genetics / Q000378:metabolism*; D020746:Calcium Channels, L-Type / Q000378:metabolism*; D020013:Calcium Signaling / Q000502:physiology; D005260:Female; D006199:Hair Cells, Auditory, Inner / Q000502:physiology*; D006309:Hearing / Q000502:physiology*; D015640:Ion Channel Gating / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D013569:Synapses / Q000502:physiology*; D009435:Synaptic Transmission / Q000502:physiology*
chemical_list: C485995:Cacna1d protein, mouse; C486058:Cacna2d2 protein, mouse; D015220:Calcium Channels; D020746:Calcium Channels, L-Type; D002118:Calcium
keywords: AMPA receptor; Cacna2d2; GluA4; PSD-95; inner hair cell; ribbon synapse