Department of Neuroscience, Cell Biology and Physiology, Wright State University, Boonshoft School of Medicine, 3640 Colonel Glenn Highway, Dayton, OH 45435, USA.
Department of Animal Morphology and Physiology, Sao Paulo State University - UNESP/FCAV, Jaboticabal, SP, Brazil.
Neuroscience. 2018 Jun 15;381:59-78. doi: 10.1016/j.neuroscience.2018.03.031. Epub 2018 Apr 24.
The cellular mechanisms by which LC neurons respond to hypercapnia are usually attributed to an "accelerator" whereby hypercapnic acidosis causes an inhibition of K channels or activation of Na and Ca channels to depolarize CO-sensitive neurons. Nevertheless, it is still unknown if this "accelerator" mechanism could be controlled by a brake phenomenon. Whole-cell patch clamping, fluorescence imaging microscopy and plethysmography were used to study the chemosensitive response of the LC neurons. Hypercapnic acidosis activates L-type Ca channels and large conductance Ca-activated K (BK) channels, which function as a "brake" on the chemosensitive response of LC neurons. Our findings indicate that both Ca and BK currents develop over the first 2 weeks of postnatal life in rat LC slices and that this brake pathway may cause the developmental decrease in the chemosensitive firing rate response of LC neurons to hypercapnic acidosis. Inhibition of this brake by paxilline (BK channel inhibitor) returns the magnitude of the chemosensitive firing rate response from LC neurons in rats older than P10 to high values similar to those in LC neurons from younger rats. Inhibition of BK channels in LC neurons by bilateral injections of paxilline into the LC results in a significant increase in the hypercapnic ventilatory response of adult rats. Our findings indicate that a BK channel-based braking system helps to determine the chemosensitive respiratory drive of LC neurons and contributes to the hypercapnic ventilatory response. Perhaps, abnormalities of this braking system could result in hypercapnia-induced respiratory disorders and panic responses.
LC 神经元对高碳酸血症反应的细胞机制通常归因于“加速器”，即高碳酸性酸中毒会抑制 K 通道或激活 Na 和 Ca 通道，使 CO 敏感神经元去极化。然而，目前尚不清楚这种“加速器”机制是否可以受到制动现象的控制。全细胞膜片钳、荧光成像显微镜和体积描记术用于研究 LC 神经元的化学敏感性反应。高碳酸性酸中毒激活 L 型 Ca 通道和大电导 Ca 激活的 K（BK）通道，作为 LC 神经元化学敏感性反应的“制动”。我们的研究结果表明，在大鼠 LC 切片中，Ca 和 BK 电流在出生后 2 周内逐渐发展，这种制动途径可能导致 LC 神经元对高碳酸性酸中毒的化学敏感性放电率反应在发育过程中降低。通过 paxilline（BK 通道抑制剂）抑制这种制动作用，可使出生后 10 天以上的大鼠 LC 神经元的化学敏感性放电率反应幅度恢复到与年轻大鼠 LC 神经元相似的高值。通过向 LC 双侧注射 paxilline 抑制 LC 神经元中的 BK 通道，可使成年大鼠的高碳酸通气反应显著增加。我们的研究结果表明，基于 BK 通道的制动系统有助于确定 LC 神经元的化学敏感性呼吸驱动，并有助于高碳酸通气反应。也许，这种制动系统的异常可能导致高碳酸血症引起的呼吸障碍和恐慌反应。
