On March 10, 2011, Neuron published a research article entitled "Follistatin-like 1 suppresses sensory afferent transmission by activating Na⁺, K⁺-ATPase". This work was carried out by postdoctoral fellow Dr. Kai-Cheng Li, and graduate students Fang-Xiong Zhang, Chang-Lin Li and Feng Wang and co-workers from Dr. Xu Zhang's laboratory at the Institution of Neuroscience, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences. They found that follistatin-like 1 (FSTL1) released from nociceptive afferent terminals negatively regulates sensory transmission by activating the presynaptic Na⁺, K⁺-ATPase (Na⁺-K⁺ pump). 

Na⁺-K⁺ pump plays a crucial role in maintaining the Na⁺ and K⁺ gradient across the plasma membrane. This gradient is essential for maintaining the resting membrane potential and excitable properties of neurons. Na⁺-K⁺ pump activity is regulated by direct modulators (ATP, Na⁺, K⁺ and cardiotonic steroid inhibitor ouabain and digoxin) and indirect modulators (catecholamines, insulin, angiotensin II and morphine) through receptor-mediated mechanisms. However, it is unclear whether Na⁺-K⁺ pump could be regulated by any agonists expressed in neurons or other cells in the body.

Li et al. found that FSTLl was highly expressed in small-diameter neurons of the dorsal root ganglion (DRG). FSTL1 was transported to the afferent terminals via small translucent vesicles and secreted in both spontaneous and depolarization-induced manners. Interestingly, FSTL1 was found to bind the α1 subunit of Na⁺-K⁺ pump and elevate pump activity. Extracellular FSTL1 induced membrane hyperpolarization in cultured cells and inhibited afferent synaptic transmission in spinal cord slices by activating the Na⁺-K⁺ pump. In close collaboration with Dr. Xiang Gao's laboratory at Nanjing University, they generated conditional deletion of FSTL1 in small DRG neurons of mice. These mutant mice displayed enhancement of afferent synaptic transmission and sensory hypersensitivity. Thus, FSTL1-dependent activation of Na⁺-K⁺ pump regulates the threshold of somatic sensation, suggesting that the function of nervous system could be modulated by an endogenous Na⁺-K⁺ pump activator which regulates synaptic transmission.

This work was supported by the grants from the Chinese Academy of Sciences, the Ministry of Science and Technology and the Natural Science Foundation of China.

Proposed model of the FSTL1-Na⁺, K⁺-ATPase system for regulating synaptic transmission. Membrane depolarization triggers Ca²⁺-dependent exocytosis of synaptic vesicles and FSTL1 vesicles. Secreted FSTL1 directly activates the presynaptic α1 subunit of Na⁺, K⁺-ATPase to hyperpolarize the membrane (ΔVm) and reduce Ca²⁺ influx, enabling an inhibitory regulation of synaptic transmission.