Blockade of Na^+/H^+ exchanger type 3 causes intracellular acidification and hyperexcitability via inhibition of pH-sensitive K^+ channels in chemosensitive respiratory neurons of the dorsal vagal nucleus in rats  

作　　者：Jing Zhang Hui Peng Sigrid C.Veasey Jing Ma Guang-Fa Wang Ke-Wei Wang 

机构地区：[1]Department of Respiratory and Critical Care Medicine, Peking University First Hospital [2]Departments of Neurobiology and Molecular and Cellular Pharmacology, Peking University Health Science Center [3]Center for Sleep and Circadian Neurobiology,University of Pennsylvania School of Medicine [4]Department of Medicine, University of Pennsylvania School of Medicine

出　　处：《Neuroscience Bulletin》2014年第1期43-52,共10页神经科学通报（英文版）

基　　金：supported by the National Natural Science Foundation of China(30900646 and 81241004)

摘　　要：Extracellular pH （pHe） and intracellular pH （pHi） are important factors for the excitability of chemosensitive central respiratory neurons that play an important role in respiration and obstructive sleep apnea. It has been proposed that inhibition of central Na^＋/ H^＋ exchanger 3 （NHE-3）, a key pHi regulator in the brainstem, decreases the pH, leading to membrane depolarization for the maintenance of respiration. However, how intracellular pH affects the neuronal excitability of respiratory neurons remains largely unknown. In this study, we showed that NHE-3 mRNA is widely distributed in respiration-related neurons of the rat brainstem, including the dorsal vagal nucleus （DVN）. Whole-cell patch clamp recordings from DVN neurons in brain slices revealed that the standing outward current （Iso） through pH-sensitive K^＋ channels was inhibited in the presence of the specific NHE-3 inhibitor AVE0657 that decreased the pHi. Exposure of DVN neurons to an acidified PIle and AVE0657 （5 μmol/L） resulted in a stronger effect on firing rate and Iso than acidified pHe alone. Taken together, our results showed that intracellular acidification by blocking NHE-3 results in inhibition of a pH- sensitive K^＋ current, leading to synergistic excitation of chemosensitive DVN neurons for the regulation of respiration.Extracellular pH （pHe） and intracellular pH （pHi） are important factors for the excitability of chemosensitive central respiratory neurons that play an important role in respiration and obstructive sleep apnea. It has been proposed that inhibition of central Na^＋/ H^＋ exchanger 3 （NHE-3）, a key pHi regulator in the brainstem, decreases the pH, leading to membrane depolarization for the maintenance of respiration. However, how intracellular pH affects the neuronal excitability of respiratory neurons remains largely unknown. In this study, we showed that NHE-3 mRNA is widely distributed in respiration-related neurons of the rat brainstem, including the dorsal vagal nucleus （DVN）. Whole-cell patch clamp recordings from DVN neurons in brain slices revealed that the standing outward current （Iso） through pH-sensitive K^＋ channels was inhibited in the presence of the specific NHE-3 inhibitor AVE0657 that decreased the pHi. Exposure of DVN neurons to an acidified PIle and AVE0657 （5 μmol/L） resulted in a stronger effect on firing rate and Iso than acidified pHe alone. Taken together, our results showed that intracellular acidification by blocking NHE-3 results in inhibition of a pH- sensitive K^＋ current, leading to synergistic excitation of chemosensitive DVN neurons for the regulation of respiration.

关 键 词：Na^＋/H^＋ exchange potassium channel dorsal vagal nucleus in situ hybridization respiration 

分 类 号：R332[医药卫生—人体生理学]