Functional disorders of the sympathetic nervous system in mice lacking the α1B subunit (Cav 2.2) of N-type calcium channels
Functional disorders of the sympathetic nervous system in mice lacking the α1B subunit (Cav 2.2) of N-type calcium channels
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DOI：
10.1073/pnas.081089398
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发表时间：
2001-04-24
影响因子：
11.1
通讯作者：
Mori, Y
中科院分区：
文献类型：
--
作者：
Ino, M;Yoshinaga, T;Mori, Y
N型电压依赖性钙通道（VDCCs）主要分布于神经系统，在神经元的多种功能中发挥重要作用，包括交感神经末梢的神经递质释放。作为阐明N型VDCC的生理学意义的直接方法，我们已经产生了α（1B）亚基（Cav 2.2）遗传缺陷的小鼠。令人惊讶的是，规则缺陷的无效小鼠具有正常的寿命并且没有明显的行为缺陷。观察到对ω-芋螺毒素GVIA敏感的N-型电流的完全和选择性消除，而突变小鼠的神经元制备物中其他VDCC类型的活性没有显著变化。双侧颈动脉阻断后，由交感神经系统介导的压力反射反应明显减弱。在N-型缺陷小鼠的离体左心房，电刺激交感神经元引起的正性变力反应明显减弱。相比之下，突变小鼠的副交感神经活动与野生型小鼠几乎相同。有趣的是，突变小鼠的心率和血压持续升高。这些结果提供了直接的证据，N型VDCC是不可缺少的交感神经系统的功能，在循环调节，并表明，N型VDCC缺陷小鼠将是一个有用的模型，用于研究疾病归因于交感神经功能障碍。
N-type voltage-dependent Ca2+ channels (VDCCs), predominantly localized in the nervous system, have been considered to play an essential role in a variety of neuronal functions, including neurotransmitter release at sympathetic: nerve terminals. As a direct approach to elucidating the physiological significance of N-type VDCCs, we have generated mice genetically deficient in the alpha (1B) subunit (Cav 2.2), The rule-deficient null mice, surprisingly, have a normal life span and are free from apparent behavioral defects. A complete and selective elimination of N-type currents, sensitive to omega -conotoxin GVIA, was observed without significant changes in the activity of other VDCC types in neuronal preparations of mutant mice. The baroreflex response, mediated by the sympathetic nervous system, was markedly reduced after bilateral carotid occlusion, In isolated left atria prepared from N-type-deficient mice, the positive inotropic responses to electrical sympathetic neuronal stimulation were dramatically decreased compared with those of normal mice. In contrast, parasympathetic nervous activity in the mutant mice was nearly identical to that of wild-type mice. Interestingly, the mutant mice showed sustained elevation of heart rate and blood pressure. These results provide direct evidence that N-type VDCCs are indispensable for the function of the sympathetic nervous system in circulatory regulation and indicate that N-type VDCC-deficient mice will be a useful model for studying disorders attributable to sympathetic nerve dysfunction.