title: Stable respiratory activity requires both P/Q-type and N-type voltage-gated calcium channels.
abstract: P/Q-type voltage-gated calcium channels (Ca(v)2.1) 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 Ca(v)2.1 pore-forming α(1A) subunit (α(1A)⁻/⁻) encoded by CACNA1a (Jun et al., 1999) suffer during postnatal development from increasing breathing disturbances 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-Bötzinger complex. The loss of Ca(v)2.1 was associated with an alteration in the functional dependency on N-type calcium channels (Ca(v)2.2). 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 α(1A)⁻/⁻ mice. The amplitude of evoked EPSPs was smaller in inspiratory neurons from α(1A)⁻/⁻ mice compared with CTs. Conotoxin GVIA abolished all EPSPs in inspiratory neurons from α(1A)⁻/⁻ 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 α(1A)⁻/⁻ 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.
authors: Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, Washington 98101, USA.
authors: Henner
authors: H
authors: Koch
authors: Sebastien
authors: S
authors: Zanella
authors: Gina E
authors: GE
authors: Elsen
authors: Lincoln
authors: L
authors: Smith
authors: Atsushi
authors: A
authors: Doi
authors: Alfredo J
authors: AJ
authors: Garcia
authors: Aguan D
authors: AD
authors: Wei
authors: Randy
authors: R
authors: Xun
authors: Sarah
authors: S
authors: Kirsch
authors: Christopher M
authors: CM
authors: Gomez
authors: Robert F
authors: RF
authors: Hevner
authors: Jan-Marino
authors: JM
authors: Ramirez
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001933:Brain Stem / Q000502:physiology; D020864:Calcium Channels, N-Type / Q000172:deficiency / Q000502:physiology*; D020865:Calcium Channels, P-Type / Q000172:deficiency / Q000502:physiology; D020907:Calcium Channels, Q-Type / Q000172:deficiency / Q000502:physiology; D019706:Excitatory Postsynaptic Potentials / Q000235:genetics / Q000502:physiology; D005260:Female; D008297:Male; D051379:Mice; D057507:Mice, 129 Strain; D018345:Mice, Knockout; D009924:Organ Culture Techniques; D015656:Respiratory Mechanics / Q000235:genetics / Q000502:physiology*
chemical_list: D020864:Calcium Channels, N-Type; D020865:Calcium Channels, P-Type; D020907:Calcium Channels, Q-Type; C500963:Cacna1b protein, mouse