Abstract
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.
Highlights
Acid-sensing ion channels represent an H+-gated subgroup of the amiloride-sensitive Na+ channel/degenerin family (ENaC/ DEG), a family of cation channels [1]
Our current data demonstrated that ASIC1a expressed on the orexin neurons in the lateral hypothalamus (LH) contributed to the regulation of breathing
Since 1997, when Waldmann cloned a subunit of H+gated channels (ASICs) transiently activated by rapid extracellular acidification [1], Acid-sensing ion channels (ASICs) have been considered for chemoreception
Summary
Acid-sensing ion channels represent an H+-gated subgroup of the amiloride-sensitive Na+ channel/degenerin family (ENaC/ DEG), a family of cation channels [1]. In the CNS, neurons express ASIC1a, ASIC2a, ASIC2b and ASIC4 subunits [16], but predominantly ASIC1a. In the 1950s, Redgate and Gellhorn found that injection of barbiturates into the LH reduced respiratory activity [19]. These studies established that the LH may exert an excitatory drive to respiration. Recent data revealed orexin containing neurons located in the LH were related to control of breathing and arousal [20,21]. We hypothesize that ASIC1a located on the orexin neurons in the LH contribute to the regulation of breathing by sensing local acidity. Our data support that acidification of the LH can stimulate breathing via activation of ASIC1a on orexin neurons
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