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• W3101126039 startingPage "260901" @default.
• W3101126039 abstract "Background: Regulation of brain pH is a critical homeostatic process. Changes in brain pH modulate various ion channels and receptors and thus neuronal excitability. Tissue acidosis, resulting from hypoxia or hypercapnia, can activate acid-sensing ion channels (ASICs), a family of primarily Na+ permeable ion channels, although ASIC1a homomeric channels are also permeable to Ca2+. During brain acidosis, ASIC activation produces neuronal death through a process called acidotoxicity, which acts alongside glutamate-mediated excitotoxicity. Naked mole-rats (NMRs, Heterocephalus glaber) are long-lived, fossorial, eusocial rodents that display remarkable behavioral/cellular hypoxia and hypercapnia resistance. In the central nervous system, ASIC subunit expression is similar between mouse and NMR with the exception of much lower expression of ASIC4 throughout the NMR brain. However, ASIC function and neuronal sensitivity to sustained acidosis has not been examined in the NMR brain. Results: Whole-cell patch-clamp electrophysiology of cultured NMR and mouse cortical and hippocampal neurons demonstrated that NMR neurons have smaller voltage-gated Na+ channel currents and more hyperpolarized resting membrane potentials. We further demonstrate that acid-mediated currents in NMR neurons are of smaller magnitude than in mouse, and that all currents in both species are fully blocked by the ASIC antagonist benzamil. Using the ASIC1a blocker Psalmotoxin-1 (PcTx1), we find that ASIC1a plays a major role in ASIC-mediated currents in mouse neurons, whereas in NMR neurons, only a few responses were blocked by 10 nM PcTx1. However, when nmrASIC1a was heterologously expressed in Chinese hamster ovary cells, neither 10 nor 100 nM PcTx1 inhibited acid-evoked currents. We also show that nmrASIC1a channel is Ca2+ permeable. Finally, we demonstrate that NMR neurons show greater resistance to acid-induced cell death than mouse neurons. Conclusions: NMR neurons are less excitable than mouse neurons and show significant cellular resistance to acidotoxicity, likely resulting from smaller ASIC-mediated currents, which may be neuroprotective against acid-induced neuronal death." @default.
• W3101126039 created "2020-11-23" @default.
• W3101126039 creator A5016652907 @default.
• W3101126039 creator A5030265237 @default.
• W3101126039 date "2018-02-06" @default.
• W3101126039 modified "2023-09-23" @default.
• W3101126039 title "Naked mole-rat brain neurons have reduced ASIC-mediated currents and are resistant to acid-induced cell death" @default.
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