Growth Differentiation Factor-15 Produces Analgesia by Inhibiting Tetrodotoxin-Resistant Nav1.8 Sodium Channel Activity in Rat Primary Sensory Neurons
Wei Lin1 • Wen-Wen Zhang1 • Ning Lyu1 • Hong Cao1 • Wen-Dong Xu1,2 • Yu-Qiu Zhang1,3
1 Department of Translational Neuroscience, Jing’an District Centre Hospital of Shanghai, State Key Laboratory of Medical Neurobiology and Institutes of Brain Science, Fudan University, Shanghai 200032, China
2 Department of Hand Surgery, Huashan Hospital, Fudan University, Shanghai 200040, China
3 Department of Neurobiology, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai 200032, China
Abstract
Growth differentiation factor 15 (GDF-15) is a member of the transforming growth factor-b superfamily. It is widely distributed in the central and peripheral nervous systems. Whether and how GDF-15 modulates nociceptive signaling remains unclear. Behaviorally, we found that peripheral GDF-15 significantly elevated nociceptive response thresholds to mechanical and thermal stimuli in naı¨ve and arthritic rats. Electrophysiologically, we demonstrated that GDF-15 decreased the excitability of smalldiameter dorsal root ganglia (DRG) neurons. Furthermore, GDF-15 concentration-dependently suppressed tetrodotoxin-resistant sodium channel Nav1.8 currents, and shifted the steady-state inactivation curves of Nav1.8 in a hyperpolarizing direction. GDF-15 also reduced window currents and slowed down the recovery rate of Nav1.8 channels, suggesting that GDF-15 accelerated inactivation and slowed recovery of the channel. Immunohistochemistry results showed that activin receptor-like kinase-2 (ALK2) was widely expressed in DRG medium- and smalldiameter neurons, and some of them were Nav1.8-positive. Blockade of ALK2 prevented the GDF-15-induced inhibition of Nav1.8 currents and nociceptive behaviors. Inhibition of PKA and ERK, but not PKC, blocked the inhibitory effect of GDF-15 on Nav1.8 currents. These results suggest a functional link between GDF-15 and Nav1.8 in DRG neurons via ALK2 receptors and PKA associated with MEK/ERK, which mediate the peripheral analgesia of GDF-15.
Keywords
Growth differentiation factor-15;Tetrodotoxin-resistant sodium channel;Nav1.8; Dorsal root ganglion; Whole-cell recording; Activin receptor-like kinase-2;Pain
