Research Article: Role of acid-sensing ion channels in hypoxia- and hypercapnia-induced ventilatory responses

Date Published: February 23, 2018

Publisher: Public Library of Science

Author(s): Neil D. Detweiler, Kenneth G. Vigil, Thomas C. Resta, Benjimen R. Walker, Nikki L. Jernigan, Yu Ru Kou.


Previous reports indicate roles for acid-sensing ion channels (ASICs) in both peripheral and central chemoreception, but the contributions of ASICs to ventilatory drive in conscious, unrestrained animals remain largely unknown. We tested the hypotheses that ASICs contribute to hypoxic- and hypercapnic-ventilatory responses. Blood samples taken from conscious, unrestrained mice chronically instrumented with femoral artery catheters were used to assess arterial O2, CO2, and pH levels during exposure to inspired gas mixtures designed to cause isocapnic hypoxemia or hypercapnia. Whole-body plethysmography was used to monitor ventilatory parameters in conscious, unrestrained ASIC1, ASIC2, or ASIC3 knockout (-/-) and wild-type (WT) mice at baseline, during isocapnic hypoxemia and during hypercapnia. Hypercapnia increased respiratory frequency, tidal volume, and minute ventilation in all groups of mice, but there were no differences between ASIC1-/-, ASIC2-/-, or ASIC3-/- and WT. Isocapnic hypoxemia also increased respiratory frequency, tidal volume, and minute ventilation in all groups of mice. Minute ventilation in ASIC2-/- mice during isocapnic hypoxemia was significantly lower compared to WT, but there were no differences in the responses to isocapnic hypoxemia between ASIC1-/- or ASIC3-/- compared to WT. Surprisingly, these findings show that loss of individual ASIC subunits does not substantially alter hypercapnic or hypoxic ventilatory responses.

Partial Text

Arterial O2, CO2, and pH (PaO2, PaCO2, and pHa) homeostasis is maintained by reflex control of ventilation. Alterations in PaO2, PaCO2, and pHa are detected by peripheral chemoreceptors located in type I glomus cells within the carotid and aortic bodies. PaCO2 homeostasis is additionally regulated by central chemoreceptors located on the ventral surface of the medulla as well as other brain regions [1]. Activation of carotid chemoreceptors in response to hypoxemia, hypercapnia, or acidosis leads to inhibition of K+ channels, depolarization of the chemoreceptor cells, activation of L-type Ca2+ channels, and release of excitatory neurotransmitters that subsequently stimulate ventilation and sympathetic activation [2–8]. Although this model of carotid body chemoreception is generally accepted, there are several O2- and CO2/pH-sensitive ion channels and other proteins and their individual and integrated roles in chemoreception remain incompletely understood. The precise location of central chemoreception also remains uncertain, and it appears that several brain regions are involved [1]. A major mechanism by which central chemoreceptors detect CO2 levels is thought to be the detection of secondary changes in cerebrospinal fluid pH [1]. Ion channels are generally the favored candidates for central chemoreception [9], but the identity of the specific channels involved remains unclear, with several candidates having been proposed [10–13]. One family of ion channels implicated in both peripheral and central chemoreception is that of the proton-gated, acid-sensing ion channels (ASICs).

Previous evidence indicates that ASICs are involved in chemoreception and the control of ventilation [16–19,23,24], but most of this evidence comes from in vitro studies and little is known about the role of ASICs in hypercapnic and hypoxic ventilatory responses in conscious animals. Here we directly measured hypercapnic and hypoxic ventilatory responses in conscious, unrestrained mice. In contrast to our hypothesis, we found that genetic deletion of ASIC1, 2, or 3 does not alter the hypercapnic ventilatory response in mice; whereas ASIC2 appears to play a minor role in the hypoxic ventilatory response. Together, these data suggest the contribution of ASICs to ventilatory control is modest.




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