Department of Physiology and Cellular Biophysics, Columbia University College of Physicians and Surgeons, New York, United States; Medical Scientist Training Program, Columbia University, New York, United States
Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, United States
Stephanie M Campos
Neurobiology Course, Marine Biological Laboratory, Woods Hole, United States
Ellen A Lumpkin
Department of Physiology and Cellular Biophysics, Columbia University College of Physicians and Surgeons, New York, United States; Neurobiology Course, Marine Biological Laboratory, Woods Hole, United States
Rachel B Brem
Department of Plant and Microbial Biology, University of California, Berkeley, Berkeley, United States; Buck Institute for Research on Aging, Novato, United States
Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, United States; Neurobiology Course, Marine Biological Laboratory, Woods Hole, United States; Helen Wills Neuroscience Institute, University of California, Berkeley, Berkeley, United States
Somatosensory neurons mediate responses to diverse mechanical stimuli, from innocuous touch to noxious pain. While recent studies have identified distinct populations of A mechanonociceptors (AMs) that are required for mechanical pain, the molecular underpinnings of mechanonociception remain unknown. Here, we show that the bioactive lipid sphingosine 1-phosphate (S1P) and S1P Receptor 3 (S1PR3) are critical regulators of acute mechanonociception. Genetic or pharmacological ablation of S1PR3, or blockade of S1P production, significantly impaired the behavioral response to noxious mechanical stimuli, with no effect on responses to innocuous touch or thermal stimuli. These effects are mediated by fast-conducting A mechanonociceptors, which displayed a significant decrease in mechanosensitivity in S1PR3 mutant mice. We show that S1PR3 signaling tunes mechanonociceptor excitability via modulation of KCNQ2/3 channels. Our findings define a new role for S1PR3 in regulating neuronal excitability and establish the importance of S1P/S1PR3 signaling in the setting of mechanical pain thresholds.
