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Deletion of the Ca2+ Channel Subunit alpha(2)delta 3 Differentially Affects Ca(v)2.1 and Ca(v)2.2 Currents in Cultured Spiral Ganglion Neurons Before and After the Onset of Hearing
Obermair, Gerald J.
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Voltage-gated Ca2+ channels are composed of a pore-forming alpha(1) subunit and auxiliary beta and alpha(2)delta subunits, which modulate Ca2+ current properties and channel trafficking. So far, the partial redundancy and specificity of alpha(1) for alpha(2)delta subunits in the CNS have remained largely elusive. Mature spiral ganglion (SG) neurons express alpha(2)delta subunit isoforms 1, 2, and 3 and multiple Ca2+ channel subtypes. Differentiation and in vivo functions of their endbulb of Held synapses, which rely on presynaptic P/Q channels (Lin et al., 2011), require the alpha(2)delta 3 subunit (Pirone et al., 2014). This led us to hypothesize that P/Q channels may preferentially co-assemble with alpha(2)delta 3. Using a dissociated primary culture, we analyzed the effects of alpha(2)delta 3 deletion on somatic Ca2+ currents (I-Ca) of SG neurons isolated at postnatal day 20 (P20), when the cochlea is regarded to be mature. P/Q currents were the dominating steady-state Ca2+ currents (54% of total) followed by T-type, L-type, N-type, and R-type currents. Deletion of alpha(2)delta 3 reduced P/Q- and R-type currents by 60 and 38%, respectively, whereas L-type, N-type, and T-type currents were not altered. A subset of I-Ca types was also analyzed in SG neurons isolated at P5, i.e., before the onset of hearing (P12). Both L-type and N-type current amplitudes of wildtype SG neurons were larger at P5 compared with P20. Deletion of alpha(2)delta 3 reduced L-type and N-type currents by 23 and 44%, respectively. In contrast, small P/Q currents, which were just being up-regulated at P5, were unaffected by the lack of alpha(2)delta 3. In summary, alpha(2)delta 3 regulates amplitudes of L- and N-type currents of immature cultured SG neurons, whereas it regulates P/Q- and R-type currents at P20. Our data indicate a developmental switch from dominating somatic N- to P/Q-type currents in cultured SG neurons. A switch from N- to P/Q-type channels, which has been observed at several central synapses, may also occur at developing endbulbs of Held. In this case, reduction of both neonatal N-(P5) and more mature P/Q-type currents (around/after hearing onset) may contribute to the impaired morphology and function of endbulb synapses in alpha(2)delta 3-deficient mice.