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- Title
Stable Respiratory Activity Requires Both P/Q-Type and N-Type Voltage-Gated Calcium Channels.
- Authors
Koch, Henner; Zanella, Sebastien; Elsen, Gina E.; Smith, Lincoln; Doi, Atsushi; Garcia III, Alfredo J.; Wei, Aguan D.; Xun, Randy; Kirsch, Sarah; Gomez, Christopher M.; Hevner, Robert F.; Ramirez, Jan-Marino
- Abstract
P/Q-type voltage-gated calcium channels (Cav2.1) play critical presynaptic and postsynaptic roles throughout the nervous system and have been implicated in a variety of neurological disorders. Here we report that mice with a genetic ablation of the Cav2.1 pore-forming α1A subunit (α1A-/- ) encoded by CACNAla (Jun et al., 1999) suffer during postnatal development from increasing breathing distur-bances that lead ultimately to death. Breathing abnormalities include decreased minute ventilation and a specific loss of sighs, which was associated with lung atelectasis. Similar respiratory alterations were preserved in the isolated in vitro brainstem slice preparation containing the pre-Botzinger complex. The loss of Cav2.1 was associated with an alteration in the functional dependency on N-type calcium channels (Cav2.2). Blocking N-type calcium channels with conotoxin GVIA had only minor effects on respiratory activity in slices from control (CT) littermates, but abolished respiratory activity in all slices from u1A mice. The amplitude of evoked EPSPs was smaller in inspiratory neurons from a α1A-/- mice compared with CTs. Conotoxin GVIA abolished all EPSPs in inspiratory neurons from α1A-/- mice, while the EPSP amplitude was reduced by only 30% in CT mice. Moreover, neuromodulation was significantly altered as muscarine abolished respiratory network activity in α1A-/- mice but not in CT mice. We conclude that excitatory synaptic transmission dependent on N-type and P/Q-type calcium channels is required for stable breathing and sighing. In the absence of P/Q-type calcium channels, breathing, sighing, and neuromodulation are severely compromised, leading to early mortality.
- Subjects
CONOTOXINS; CALCIUM channels; PRESYNAPTIC receptors; NEUROLOGICAL disorders; POSTSYNAPTIC density protein; ATELECTASIS; BRAIN stem
- Publication
Journal of Neuroscience, 2013, Vol 33, Issue 8, p3633
- ISSN
0270-6474
- Publication type
Article
- DOI
10.1523/JNEUROSCI.6390-11.2013