alpha sub(2) delta 2 Controls the Function and Trans-Synaptic Coupling of Ca sub(v) 1.3 Channels in Mouse Inner Hair Cells and Is Essential for Normal Hearing

• Published in: The Journal of neuroscience 2016-10, Vol.36 (43), p.11024-11036
• Main Authors: Fell, Barbara, Eckrich, Stephanie, Blum, Kerstin, Eckrich, Tobias, Hecker, Dietmar, Obermair, Gerald J, Munkner, Stefan, Flockerzi, Veit, Schick, Bernhard, Engel, Jutta
• Format: Article
• Language: English
• ISSN: 0270-6474; 1529-2401
• DOI: 10.1523/JNEUROSCI.3468-14.2016

The auxiliary subunit alpha sub(2) delta 2 modulates the abundance and function of voltage-gated calcium channels. Here we show that alpha sub(2) delta 2 mRNA is expressed in neonatal and mature hair cells. A functional alpha sub(2) delta 2-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 Ca super(2+) and Ba super(2+) 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 Ca sub(v) 1.3 channels normally coassemble with alpha sub(2) delta 2 at IHC presynapses. The reduction of depolarization-evoked exocytosis in du/du IHCs reflected their reduced Ca super(2+) currents. Ca super(2+)- and voltage-dependent K super(+)(BK) currents and the expression of the pore-forming BK alpha protein were normal. Ca sub(v) 1.3 and Ca sub(v) beta 2 protein expression was unchanged in du/du IHCs, forming clusters at presynaptic ribbons. However, the close apposition of presynaptic Ca sub(v) 1.3 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 Ca sub(v) 1.3 channels, the largely extracellularly localized alpha sub(2) delta 2 subunit moreover plays a so far unknown role in mediating trans-synaptic alignment of presynaptic Ca super(2+) channels and postsynaptic AMPA receptors.