Abstract
Na+,K+-ATPase (NKA) is required to generate the resting membrane potential in neurons. Nociceptive afferent neurons express not only the α and β subunits of NKA but also the γ subunit FXYD2. However, the neural function of FXYD2 is unknown. The present study shows that FXYD2 in nociceptive neurons is necessary for maintaining the mechanical allodynia induced by peripheral inflammation. FXYD2 interacted with α1NKA and negatively regulated the NKA activity, depolarizing the membrane potential of nociceptive neurons. Mechanical allodynia initiated in FXYD2-deficient mice was abolished 4 days after inflammation, whereas it persisted for at least 3 weeks in wild-type mice. Importantly, the FXYD2/α1NKA interaction gradually increased after inflammation and peaked on day 4 post inflammation, resulting in reduction of NKA activity, depolarization of neuron membrane and facilitation of excitatory afferent neurotransmission. Thus, the increased FXYD2 activity may be a fundamental mechanism underlying the persistent hypersensitivity to pain induced by inflammation.
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Acknowledgements
This work was supported by the National Natural Science Foundation of China (31130066) and the Strategic Priority Research Program (B) of Chinese Academy of Sciences (XDB01020300).
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( Supplementary information is linked to the online version of the paper on the Cell Research website.)
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Supplementary information, Figure S1
Recording of membrane potential in IB4-negative small DRG neurons. (PDF 39 kb)
Supplementary information, Figure S2
Recording of AP and AHP in IB4-positive small DRG neurons. (PDF 39 kb)
Supplementary information, Figure S3
Expression of α1 and β1 subunits of NKA, FSTL1 and FXYD2 in DRGs after peripheral inflammation. (PDF 135 kb)
Supplementary information, Figure S4
Time course of NKA activity in ATP-treated microsomes. (PDF 36 kb)
Supplementary information, Data S1
Materials and Methods (PDF 42 kb)
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Wang, F., Cai, B., Li, KC. et al. FXYD2, a γ subunit of Na+,K+-ATPase, maintains persistent mechanical allodynia induced by inflammation. Cell Res 25, 318–334 (2015). https://doi.org/10.1038/cr.2015.12
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DOI: https://doi.org/10.1038/cr.2015.12
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