title: 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.
abstract: 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 pHi, 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 pHe 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.
authors.affiliation: Department of Respiratory and Critical Care Medicine, Peking University First Hospital, Beijing, 100034, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Zhang
authors.forename: Hui
authors.initials: H
authors.lastname: Peng
authors.forename: Sigrid C
authors.initials: SC
authors.lastname: Veasey
authors.forename: Jing
authors.initials: J
authors.lastname: Ma
authors.forename: Guang-Fa
authors.initials: GF
authors.lastname: Wang
authors.forename: Ke-Wei
authors.initials: KW
authors.lastname: Wang
mesh_terms: D000818:Animals; D001933:Brain Stem / Q000378:metabolism / Q000502:physiology*; D002628:Chemoreceptor Cells / Q000378:metabolism / Q000502:physiology*; D006863:Hydrogen-Ion Concentration; D007424:Intracellular Fluid / Q000378:metabolism; D015221:Potassium Channels / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012125:Respiratory Center / Q000378:metabolism / Q000502:physiology; D000074083:Sodium-Hydrogen Exchanger 3; D017923:Sodium-Hydrogen Exchangers / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D015221:Potassium Channels; C000613387:Slc9a3 protein, rat; D000074083:Sodium-Hydrogen Exchanger 3; D017923:Sodium-Hydrogen Exchangers