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Acid‐Sensing Ion Channels: Mediator of Cerebrovascular Responses to CO 2
Author(s) -
Faraci Frank,
Taugher Rebecca,
Fan Rong,
Wemmie John
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.836.15
Subject(s) - acid sensing ion channel , vasodilation , ion channel , chemistry , mediator , acidosis , nitric oxide , microbiology and biotechnology , cerebral blood flow , neuroscience , medicine , endocrinology , pharmacology , biology , biochemistry , receptor
Because normal brain function is critically dependent on cerebral blood flow (CBF), insufficient CBF contributes to neurological dysfunction and degeneration. Carbon dioxide (CO 2 ), via effects on local acidosis, is one of the most potent regulators of CBF. Although a role for nitric oxide (NO) in intermediate signaling has been implicated, mechanisms that initiate CO 2 induced‐vasodilation remain unclear. Acid‐sensing ion channel‐1A (ASIC1A) is a proton‐gated cation channel that is activated by extracellular acidosis. Based on work that implicated ASIC1A in the amygdala and stria terminalis in CO 2 ‐ and acid‐evoked behavior, we hypothesized that ASIC1A might also mediate microvascular response to CO 2 . To test this hypothesis, we genetically and pharmacologically manipulated ASIC1A and assessed effects on CO 2 ‐induced dilation of small cerebral arterioles in vivo. Genetic deficiency in ASIC1A ( Asic1a −/− ) or local treatment with psalmotoxin (an ASIC inhibitor) in Asic1a +/+ mice eliminated the majority of the effect of 5 or 10% CO 2 on arteriolar diameter (P<0.05). Vasodilator effects of acetylcholine, which acts via endothelial NO synthase were unaffected, suggesting a non‐vascular source of NO was key for CO 2 responses. We then hypothesized that neurons may be the cell type through which ASIC1A influences microvessels. In mice in which Asic1a was specifically disrupted in neurons, effects of CO 2 on arteriolar diameter were also greatly attenuated. To further explore a role for ASIC1A in the regulation of NO production, we measured NO concentrations in whole brain lysates immediately after exposure to CO 2 . We found that 10% CO 2 induced NO production in wild‐type mice, but not in mice lacking Asic1a globally or specifically in neurons. Together, these data are consistent with a model wherein activation of neuronal ASIC1A is critical for CO 2 ‐induced NO production and vasodilation. With these findings, ASIC1A emerges as major regulator of microvascular tone in brain. Support or Funding Information This work was supported by the NIH, the Department of Veterans Affairs, and the Fondation Leducq.