Subtype-Selective Small Molecule Inhibitors Reveal a Fundamental Role for Nav1.7 in Nociceptor Electrogenesis, Axonal Conduction and Presynaptic Release

Autor: Edward B. Stevens, Zhixin Lin, Anna Wilbrey, Stephen G. Waxman, Peter J. Cox, Sulayman D. Dib-Hajj, Mark L. Chapman, Malgorzata A. Mis, Christopher William West, R. Ian Storer, Stupple Paul Anthony, Elizabeth C. Payne, Manoj K. Patel, David Printzenhoff, Andrew D. Randall, James A. Hounshell, Douglas S. Krafte, Jamie Turner, Nigel Alan Swain, Aristos J. Alexandrou, Richard P. Butt, Adam R. Brown, Mark Estacion, Brian E. Marron, Alex Gutteridge, Neil A. Castle, Rachel Doyle, Mirko Rivara
Jazyk: angličtina
Rok vydání: 2016
Předmět:
Male
0301 basic medicine
Sensory Receptors
Patch-Clamp Techniques
Physiology
Action Potentials
Social Sciences
lcsh:Medicine
Nervous System
Biochemistry
Ion Channels
Sodium Channels
Mice
0302 clinical medicine
Animal Cells
Ganglia
Spinal
Medicine and Health Sciences
Psychology
lcsh:Science
Membrane Electrophysiology
Neurons
Sulfonamides
Multidisciplinary
Organic Compounds
Chemistry
Physics
Phenyl Ethers
Monosaccharides
NAV1.7 Voltage-Gated Sodium Channel
Nociceptors
Anatomy
Electrophysiology
Bioassays and Physiological Analysis
Nociception
Spinal Cord
Physical Sciences
Nociceptor
Cell lines
Sensory Perception
Cellular Types
Biological cultures
Research Article
Signal Transduction
Carbohydrates
Biophysics
Presynaptic Terminals
Neurophysiology
Neurotransmission
Membrane Potential
03 medical and health sciences
Animals
Humans
Patch clamp
Sodium channel
Organic Chemistry
HEK 293 cells
Electrophysiological Techniques
lcsh:R
Chemical Compounds
Biology and Life Sciences
Proteins
Cell Biology
Axons
Research and analysis methods
Neuroanatomy
Glucose
HEK293 Cells
030104 developmental biology
nervous system
Cellular Neuroscience
NAV1
lcsh:Q
Patch Clamp Techniques
Neuroscience
030217 neurology & neurosurgery
Zdroj: PLoS ONE, Vol 11, Iss 4, p e0152405 (2016)
PLoS ONE
ISSN: 1932-6203
Popis: Human genetic studies show that the voltage gated sodium channel 1.7 (Nav1.7) is a key molecular determinant of pain sensation. However, defining the Nav1.7 contribution to nociceptive signalling has been hampered by a lack of selective inhibitors. Here we report two potent and selective arylsulfonamide Nav1.7 inhibitors; PF-05198007 and PF-05089771, which we have used to directly interrogate Nav1.7's role in nociceptor physiology. We report that Nav1.7 is the predominant functional TTX-sensitive Nav in mouse and human nociceptors and contributes to the initiation and the upstroke phase of the nociceptor action potential. Moreover, we confirm a role for Nav1.7 in influencing synaptic transmission in the dorsal horn of the spinal cord as well as peripheral neuropeptide release in the skin. These findings demonstrate multiple contributions of Nav1.7 to nociceptor signalling and shed new light on the relative functional contribution of this channel to peripheral and central noxious signal transmission.
Databáze: OpenAIRE
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