Stable respiratory activity requires both P/Q-type and N-type voltage-gated calcium channels.
Stable respiratory activity requires both P/Q-type and N-type voltage-gated calcium channels.
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DOI：
10.1523/jneurosci.6390-11.2013
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发表时间：
2013-02-20
期刊：
影响因子：
--
通讯作者：
Ramirez JM
中科院分区：
文献类型：
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作者：
Koch H;Zanella S;Elsen GE;Smith L;Doi A;Garcia AJ 3rd;Wei AD;Xun R;Kirsch S;Gomez CM;Hevner RF;Ramirez JM
P/Q型电压门控钙通道（Cav2.1）在整个神经系统中起着关键的突触前和突触后作用，并与多种神经系统疾病有关。在这里，我们报告了基因消融CACNA 1a编码的Cav2.1孔形成α1A亚基（α1A-/-）的小鼠在出生后发育期间遭受呼吸紊乱增加，最终导致死亡。呼吸异常包括每分钟通气量减少和特异性的叹气消失，这与肺不张有关。类似的呼吸改变保存在分离的体外脑干切片制备含有前Bötzinger复合物。Cav2.1的缺失与N型钙通道（Cav2.2）的功能依赖性改变相关。用芋螺毒素GVIA阻断N型钙通道对对照（CT）同窝小鼠切片中的呼吸活性仅有轻微影响，但在α1A−/−小鼠的所有切片中均消除了呼吸活性。与CT相比，α1A−/−小鼠吸气神经元诱发的EPSP幅度较小。芋螺毒素GVIA消除了α1A−/−小鼠吸气神经元中的所有EPSP，而CT小鼠的EPSP振幅仅降低了30%。此外，由于毒蕈碱消除了α1A−/−小鼠的呼吸网络活动，神经调节发生了显著改变，但CT小鼠没有。我们的结论是，兴奋性突触传递依赖于N型和P/Q型钙通道是需要稳定的呼吸和叹息。在缺乏P/Q型钙通道的情况下，呼吸、叹息和神经调节严重受损，导致早期死亡。
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 CACNA1a 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 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 α1A−/− mice. The amplitude of evoked EPSPs was smaller in inspiratory neurons from 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.