Nociceptive
afferent neurons of the dorsal root ganglion (DRG) express not only the α and β
subunits of Na
+,K
+-ATPase (NKA) but also the γ subunit
FXYDs. However, the localization and role of FXYDs are unclear in nociceptive
transmission of DRG neurons. The present study showed that FXYD2, one γ subunit
of NKA, is expressed in small DRG neurons, mainly in IB4
+ DRG
neurons. FXYD2 was co-localized with α1NKA in small DRG neurons. FXYD2 interacted
with the α1NKA, and negatively regulated the NKA activity in a way independent
of FSTL1. Loss of FXYD2 in
FXYD2-deficient mice caused the
hyperpolarization of membrane potential in IB4
+ small DRG neurons,
but had limited effects on the excitability of these IB4
+ neurons
under normal circumstance. Genetic deletion of FXYD2 led to the reduction of
mean frequency of spontaneous excitatory postsynaptic
currents (sEPSCs), indicating the inhibitory effects of FXYD2 on excitatory
synaptic transmission. Furthermore, FXYD2-deficient mice showed no significant
difference in basal nociceptive responses, formalin-induced acute nociceptive
responses and CFA-induced thermal hyperalgesia in comparison with the
littermates. FXYD2-deficient mice showed a normal initiation of mechanical
allodynia induced by CFA injection, but could not maintain the long-lasting
mechanical allodynia as showed in wild-type littermates. Although the
expression of FXYD2 and NKA subunits did not change after peripheral
inflammation, the interaction of FXYD2 and α1NKA was gradually increased and
reached a peak level at the fourth day after peripheral inflammation. Such
increased interaction could be responsible for reduction of NKA activity,
depolarization of membrane potential in IB4
+ small DRG neurons,
facilitation of afferent synaptic transmission and maintenance of CFA-induced
mechanical allodynia. Thus, the increased FXYD2 activity is a mechanism of the
inflammation-induced persistent mechanical allodynia.