Subtype-Selective Small Molecule Inhibitors Reveal a Fundamental Role for Nav1.7 in Nociceptor Electrogenesis, Axonal Conduction and Presynaptic Release
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 arylsulfona...
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| Veröffentlicht in: | PloS one 2016-04, Vol.11 (4), p.e0152405-e0152405 |
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| creator | Alexandrou, Aristos J Brown, Adam R Chapman, Mark L Estacion, Mark Turner, Jamie Mis, Malgorzata A Wilbrey, Anna Payne, Elizabeth C Gutteridge, Alex Cox, Peter J Doyle, Rachel Printzenhoff, David Lin, Zhixin Marron, Brian E West, Christopher Swain, Nigel A Storer, R Ian Stupple, Paul A Castle, Neil A Hounshell, James A Rivara, Mirko Randall, Andrew Dib-Hajj, Sulayman D Krafte, Douglas Waxman, Stephen G Patel, Manoj K Butt, Richard P Stevens, Edward B |
| description | 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. |
| doi_str_mv | 10.1371/journal.pone.0152405 |
| format | Article |
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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.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0152405</identifier><identifier>PMID: 27050761</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Action potential ; Action Potentials ; Anesthesiology ; Animals ; Axons ; Axons - physiology ; Biology and Life Sciences ; Brown, Mark ; Conduction ; Dorsal horn ; Ganglia, Spinal - drug effects ; Ganglia, Spinal - physiology ; Genetic aspects ; HEK293 Cells ; Humans ; Inhibitors ; Male ; Medical schools ; Medicine and Health Sciences ; Mice ; Mutation ; NAV1.7 Voltage-Gated Sodium Channel - drug effects ; NAV1.7 Voltage-Gated Sodium Channel - physiology ; Nerve conduction ; Neurons ; Neurosciences ; Nociceptors ; Pain ; Pain perception ; Patch-Clamp Techniques ; Pharmaceutical sciences ; Phenyl Ethers - pharmacology ; Physical Sciences ; Physiological aspects ; Presynaptic Terminals - physiology ; Propagation ; Research and analysis methods ; Rodents ; Signal transmission ; Signaling ; Skin ; Social Sciences ; Sodium ; Sodium channels (voltage-gated) ; Spinal cord ; Studies ; Sulfonamides - pharmacology ; Synaptic transmission ; Tetrodotoxin ; Veterans</subject><ispartof>PloS one, 2016-04, Vol.11 (4), p.e0152405-e0152405</ispartof><rights>COPYRIGHT 2016 Public Library of Science</rights><rights>2016 Alexandrou et al. This is an open access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. 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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.</description><subject>Action potential</subject><subject>Action Potentials</subject><subject>Anesthesiology</subject><subject>Animals</subject><subject>Axons</subject><subject>Axons - physiology</subject><subject>Biology and Life Sciences</subject><subject>Brown, Mark</subject><subject>Conduction</subject><subject>Dorsal horn</subject><subject>Ganglia, Spinal - drug effects</subject><subject>Ganglia, Spinal - physiology</subject><subject>Genetic aspects</subject><subject>HEK293 Cells</subject><subject>Humans</subject><subject>Inhibitors</subject><subject>Male</subject><subject>Medical schools</subject><subject>Medicine and Health Sciences</subject><subject>Mice</subject><subject>Mutation</subject><subject>NAV1.7 Voltage-Gated Sodium Channel - drug 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Database</collection><collection>Materials Science Collection</collection><collection>Publicly Available Content Database</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>Engineering Collection</collection><collection>Environmental Science Collection</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><collection>DOAJ Directory of Open Access Journals</collection><jtitle>PloS one</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Alexandrou, Aristos J</au><au>Brown, Adam R</au><au>Chapman, Mark L</au><au>Estacion, Mark</au><au>Turner, Jamie</au><au>Mis, Malgorzata A</au><au>Wilbrey, Anna</au><au>Payne, Elizabeth C</au><au>Gutteridge, Alex</au><au>Cox, Peter J</au><au>Doyle, Rachel</au><au>Printzenhoff, David</au><au>Lin, Zhixin</au><au>Marron, Brian E</au><au>West, Christopher</au><au>Swain, Nigel A</au><au>Storer, R Ian</au><au>Stupple, Paul A</au><au>Castle, Neil A</au><au>Hounshell, James A</au><au>Rivara, Mirko</au><au>Randall, Andrew</au><au>Dib-Hajj, Sulayman D</au><au>Krafte, Douglas</au><au>Waxman, Stephen G</au><au>Patel, Manoj K</au><au>Butt, Richard P</au><au>Stevens, Edward B</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Subtype-Selective Small Molecule Inhibitors Reveal a Fundamental Role for Nav1.7 in Nociceptor Electrogenesis, Axonal Conduction and Presynaptic Release</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2016-04-06</date><risdate>2016</risdate><volume>11</volume><issue>4</issue><spage>e0152405</spage><epage>e0152405</epage><pages>e0152405-e0152405</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>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.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>27050761</pmid><doi>10.1371/journal.pone.0152405</doi><tpages>e0152405</tpages><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1932-6203 |
| ispartof | PloS one, 2016-04, Vol.11 (4), p.e0152405-e0152405 |
| issn | 1932-6203 1932-6203 |
| language | eng |
| recordid | cdi_plos_journals_1779034067 |
| source | MEDLINE; DOAJ Directory of Open Access Journals; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; PubMed Central; Free Full-Text Journals in Chemistry; Public Library of Science (PLoS) |
| subjects | Action potential Action Potentials Anesthesiology Animals Axons Axons - physiology Biology and Life Sciences Brown, Mark Conduction Dorsal horn Ganglia, Spinal - drug effects Ganglia, Spinal - physiology Genetic aspects HEK293 Cells Humans Inhibitors Male Medical schools Medicine and Health Sciences Mice Mutation NAV1.7 Voltage-Gated Sodium Channel - drug effects NAV1.7 Voltage-Gated Sodium Channel - physiology Nerve conduction Neurons Neurosciences Nociceptors Pain Pain perception Patch-Clamp Techniques Pharmaceutical sciences Phenyl Ethers - pharmacology Physical Sciences Physiological aspects Presynaptic Terminals - physiology Propagation Research and analysis methods Rodents Signal transmission Signaling Skin Social Sciences Sodium Sodium channels (voltage-gated) Spinal cord Studies Sulfonamides - pharmacology Synaptic transmission Tetrodotoxin Veterans |
| title | Subtype-Selective Small Molecule Inhibitors Reveal a Fundamental Role for Nav1.7 in Nociceptor Electrogenesis, Axonal Conduction and Presynaptic Release |
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