Feng Yan, Liu Yaoyao, Cao Pan-Xiang, Sun Xun, Li Ke-Xin, Li Xin-Yu, Liu Li, Wang Hong-Dan, Cui Chang-Peng, Xiong Xue, Zhang Hao-Cheng, Qiao Guo-Fen, Li Bai-Yan
Department of Pharmacology (State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Medicine Research, Ministry of Education), Harbin Medical University School of Pharmacy, Harbin, China.
College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, China.
Neuroscience. 2020 Aug 21;442:168-182. doi: 10.1016/j.neuroscience.2020.07.003. Epub 2020 Jul 10.
Large conductance of Ca-activated K channel (KCa1.1) plays an inhibitory role in neuroexcitation. However, the expression of KCNMB4/β4-subunit in the nodose ganglia (NG) and nucleus tractus solitarius (NTS), and its effect and regulation on baroreflex afferent function at post-transcriptional level of female rats remains unknown. Here, we demonstrated that the expression of β4-subunit encoded by KCNMB4 was significantly lower in females vs. males and ovariectomized (OVX) rats in the NG. Although all baroreceptor neurons (BRNs) expressed β4-subunit, altered discharge characteristics were only observed in Ah-type neurons after ovariectomy. Notably, the decreased excitability of Ah-types was restored by paxilline and further enhanced by iberiotoxin. The consistent changes were observed in excitatory post-synaptic currents. The level of miR-504 was higher in females, which was predicted to bind to the 3'UTR of KCNMB4. In consistent, an inverse expression pattern between miR-504 and KCNMB4 was observed in baroreflex afferents. The paxilline-sensitive β4-subunits is less in Ah-types and up-regulated by ovariectomy. These data indicated that KCa1.1 β4-subunit is the key regulator in neuroexcitation of Ah-types and sexual-dimorphism in baroreflex afferent function through estrogen-dependent inhibition of KCNMB4 expression via miR-504.
大电导钙激活钾通道（KCa1.1）在神经兴奋中起抑制作用。然而，结状神经节（NG）和孤束核（NTS）中KCNMB4/β4亚基的表达，及其在转录后水平对雌性大鼠压力反射传入功能的影响和调节仍不清楚。在此，我们证明，KCNMB4编码的β4亚基在雌性大鼠与雄性大鼠以及去卵巢（OVX）大鼠的NG中的表达显著降低。虽然所有压力感受器神经元（BRN）均表达β4亚基，但去卵巢后仅在Ah型神经元中观察到放电特性改变。值得注意的是，阿弗菌素可恢复Ah型神经元降低的兴奋性，而iberiotoxin可进一步增强其兴奋性。在兴奋性突触后电流中也观察到了一致的变化。雌性大鼠中miR-504水平较高，预测其可与KCNMB4的3'UTR结合。一致的是，在压力反射传入神经中观察到miR-504与KCNMB4之间呈反向表达模式。Ah型神经元中对阿弗菌素敏感的β4亚基较少，且去卵巢后上调。这些数据表明，KCa1.1β4亚基是Ah型神经元神经兴奋和压力反射传入功能性别差异的关键调节因子，其通过miR-504对KCNMB4表达的雌激素依赖性抑制发挥作用。
