Acid sensing ion channel 1 in lateral hypothalamus contributes to breathing control.
Acid-sensing ion channels (ASICs) are present in neurons and may contribute to chemoreception. Among six subunits of ASICs, ASIC1 is mainly expressed in the central nervous system. Recently, multiple sites in the brain including the lateral hypothalamus (LH) have been found to be sensitive to extracellular acidification. Since LH contains orexin neurons and innervates the medulla respiratory center, we hypothesize that ASIC1 is expressed on the orexin neuron and contributes to acid-induced increase in respiratory drive. To test this hypothesis, we used double immunofluorescence to determine whether ASIC1 is expressed on orexin neurons in the LH, and assessed integrated phrenic nerve discharge (iPND) in intact rats in response to acidification of the LH. We found that ASIC1 was co-localized with orexinA in the LH. Microinjection of acidified artificial cerebrospinal fluid increased the amplitude of iPND by 70% (pH 7.4 v.s. pH 6.5:1.05±0.12 v.s. 1.70±0.10, n = 6, P<0.001) and increased the respiratory drive (peak amplitude of iPND/inspiratory time, PA/Ti) by 40% (1.10±0.23 v.s. 1.50±0.38, P<0.05). This stimulatory effect was abolished by blocking ASIC1 with a nonselective inhibitor (amiloride 10 mM), a selective inhibitor (PcTX1, 10 nM) or by damaging orexin neurons in the LH. Current results support our hypothesis that the orexin neuron in the LH can exert an excitation on respiration via ASIC1 during local acidosis. Since central acidification is involved in breathing dysfunction in a variety of pulmonary diseases, understanding its underlying mechanism may improve patient management.
Department of Physiology and Pathophysiology, Shanghai Medical College, Fudan University, Shanghai, China.
Nana
N
Song
Guihong
G
Zhang
Wenye
W
Geng
Zibing
Z
Liu
Weizhong
W
Jin
Li
L
Li
Yinxiang
Y
Cao
Danian
D
Zhu
Jerry
J
Yu
Linlin
L
Shen
D062646:Acid Sensing Ion Channel Blockers / Q000494:pharmacology; D062565:Acid Sensing Ion Channels / Q000235:genetics / Q000378:metabolism*; D000138:Acidosis; D000584:Amiloride / Q000494:pharmacology; D000818:Animals; D062186:Arterial Pressure / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D015870:Gene Expression; D006339:Heart Rate / Q000187:drug effects; D006863:Hydrogen-Ion Concentration; D007031:Hypothalamus / Q000187:drug effects / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008297:Male; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D009479:Neuropeptides / Q000378:metabolism; D000068797:Orexins; D010791:Phrenic Nerve / Q000187:drug effects / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012119:Respiration / Q000187:drug effects / Q000235:genetics; D012125:Respiratory Center / Q000187:drug effects / Q000378:metabolism; D056152:Respiratory Rate / Q000187:drug effects
D062646:Acid Sensing Ion Channel Blockers; D062565:Acid Sensing Ion Channels; C568268:Asic1 protein, rat; C568425:Asic2 protein, rat; D047908:Intracellular Signaling Peptides and Proteins; D009479:Neuropeptides; D000068797:Orexins; D000584:Amiloride