The dorsal root ganglion (DRG) express not only the α and β subunits of Na+,K+-ATPase (NKA) but also the γ subunit FXYD2. Our studies show that follistatin-like 1 (FSTL1) suppresses the excitatory afferent transmission by activating the α1 subunit of NKA. FSTL1 is highly expressed in small DRG neurons of mice. FSTL1 is transported to the sensory afferent terminals via small translucent vesicles and secreted in both spontaneous and depolarization-induced manners. FSTL1 binds to the α1 subunit of NKA and increases the NKA activity. Extracellular FSTL1 induces membrane hyperpolarization in cultured cells and inhibits afferent synaptic transmission in spinal cord by activating α1NKA. Genetic deletion of FSTL1 in small DRG neurons results in enhancement of afferent synaptic transmission and sensory hypersensitivity.
We also found that FXYD2 was also expressed in small DRG neurons. FXYD2 co-localized with the α1 subunit of NKA, and negatively regulated the NKA activity. In the DRG of FXYD2-deficient mice, the NKA activity was increased and the membrane potential of small neurons was hyperpolarized. Peripheral tissue inflammation resulted in reduced NKA activity and depolarized membrane potential in small DRG neurons. Moreover, the afferent synaptic transmission was facilitated, and the mechanical allodynia was long-lasting after inflammation. However, these responses could not be lasted over 4 days after inflammation in FXYD2-deficient mice, suggesting that FXYD2 is required for maintaining the inflammation-induced facilitation of excitatory afferent transmission and mechanical allodynia. Thus, the NKA activity in nociceptive afferent neurons is regulated by both the FSTL1 secretion and the FXYD2 interaction.