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K_ir 5.1-dependent CO₂ /H⁺ -sensitive currents contribute to astrocyte heterogeneity across brain regions.

ABSTRACT: Astrocyte heterogeneity is an emerging concept in which astrocytes within or between brain regions show variable morphological and/or gene expression profiles that presumably reflect different functional roles. Recent evidence indicates that retrotrapezoid nucleus (RTN) astrocytes sense changes in tissue CO_2/ H⁺ to regulate respiratory activity; however, mechanism(s) by which they do so remain unclear. Alterations in inward K⁺ currents represent a potential mechanism by which CO₂ /H⁺ signals may be conveyed to neurons. Here, we use slice electrophysiology in rats of either sex to show that RTN astrocytes intrinsically respond to CO₂ /H⁺ by inhibition of an inward rectifying potassium (K_ir ) conductance and depolarization of the membrane, while cortical astrocytes do not exhibit such CO₂ /H⁺ -sensitive properties. Application of Ba²⁺ mimics the effect of CO₂ /H⁺ on RTN astrocytes as measured by reductions in astrocyte K_ir -like currents and increased RTN neuronal firing. These CO₂ /H⁺ -sensitive currents increase developmentally, in parallel to an increased expression in K_ir 4.1 and K_ir 5.1 in the brainstem. Finally, the involvement of K_ir 5.1 in the CO₂ /H⁺ -sensitive current was verified using a Kir5.1 KO rat. These data suggest that K_ir inhibition by CO₂ /H⁺ may govern the degree to which astrocytes mediate downstream chemoreceptive signaling events through cell-autonomous mechanisms. These results identify K_ir channels as potentially important regional CO₂ /H⁺ sensors early in development, thus expanding our understanding of how astrocyte heterogeneity may uniquely support specific neural circuits and behaviors.

SUBMITTER: Patterson KC

PROVIDER: S-EPMC8665280 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:RationaleThe cardiac sodium channel NaV1.5, encoded by SCN5A, produces the rapidly inactivating depolarizing current INa that is responsible for the initiation and propagation of the cardiac action potential. Acquired and inherited dysfunction of NaV1.5 results in either decreased peak INa or increased residual late INa (INa,L), leading to tachy/bradyarrhythmias and sudden cardiac death. Previous studies have shown that increased cellular NAD+ and NAD+/NADH ratio increase INa through suppression of mitochondrial reactive oxygen species and PKC-mediated NaV1.5 phosphorylation. In addition, NAD+-dependent deacetylation of NaV1.5 at K1479 by Sirtuin 1 increases NaV1.5 membrane trafficking and INa. The role of NAD+ precursors in modulating INa remains unknown.ObjectiveTo determine whether and by which mechanisms the NAD+ precursors nicotinamide riboside (NR) and nicotinamide (NAM) affect peak INa and INa,Lin vitro and cardiac electrophysiology in vivo.Methods and resultsThe effects of NAD+ precursors on the NAD+ metabolome and electrophysiology were studied using HEK293 cells expressing wild-type and mutant NaV1.5, rat neonatal cardiomyocytes (RNCMs), and mice. NR increased INa in HEK293 cells expressing NaV1.5 (500 μM: 51 ± 18%, p = .02, 5 mM: 59 ± 22%, p = .03) and RNCMs (500 μM: 60 ± 26%, p = .02, 5 mM: 74 ± 39%, p = .03) while reducing INa,L at the higher concentration (RNCMs, 5 mM: -45 ± 11%, p = .04). NR (5 mM) decreased NaV1.5 K1479 acetylation but increased INa in HEK293 cells expressing a mutant form of NaV1.5 with disruption of the acetylation site (NaV1.5-K1479A). Disruption of the PKC phosphorylation site abolished the effect of NR on INa. Furthermore, NAM (5 mM) had no effect on INa in RNCMs or in HEK293 cells expressing wild-type NaV1.5, but increased INa in HEK293 cells expressing NaV1.5-K1479A. Dietary supplementation with NR for 10-12 weeks decreased QTc in C57BL/6 J mice (0.35% NR: -4.9 ± 2.0%, p = .14; 1.0% NR: -9.5 ± 2.8%, p = .01).ConclusionsNAD+ precursors differentially regulate NaV1.5 via multiple mechanisms. NR increases INa, decreases INa,L, and warrants further investigation as a potential therapy for arrhythmic disorders caused by NaV1.5 deficiency and/or dysfunction.

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K_ir 5.1-dependent CO₂ /H⁺ -sensitive currents contribute to astrocyte heterogeneity across brain regions.

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Kir 5.1-dependent CO2 /H+ -sensitive currents contribute to astrocyte heterogeneity across brain regions.

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OmicsDI is part of the ELIXIR infrastructure

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K_ir 5.1-dependent CO₂ /H⁺ -sensitive currents contribute to astrocyte heterogeneity across brain regions.