Subtype-selective small molecule inhibitors reveal a fundamental role for Nav1.7 in nociceptor electrogenesis, axonal conduction and presynaptic release

Aristos J. Alexandrou, Adam R. Brown, Mark L. Chapman, Mark Estacion, Jamie Turner, Malgorzata A. Mis, Anna Wilbrey, Elizabeth C. Payne, Alex Gutteridge, Peter John Cox, Rachel Doyle, David Printzenhoff, Zhixin Lin, Brian E. Marron, Christopher West, Nigel A. Swain, R. Ian Storer, Paul A. Stupple, Neil A. Castle, James A. Hounshell & 8 others Mirko Rivara, Andrew Randall, Sulayman D. Dib-Hajj, Douglas S. Krafte, Stephen G. Waxman, Manoj K. Patel, Richard P. Butt, Edward B. Stevens

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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.

Original languageEnglish
Article numbere0152405
Number of pages22
JournalPLoS ONE
Volume11
Issue number4
DOIs
Publication statusPublished - 1 Apr 2016

Cite this

Alexandrou, A. J., Brown, A. R., Chapman, M. L., Estacion, M., Turner, J., Mis, M. A., ... Stevens, E. B. (2016). Subtype-selective small molecule inhibitors reveal a fundamental role for Nav1.7 in nociceptor electrogenesis, axonal conduction and presynaptic release. PLoS ONE, 11(4), [e0152405]. https://doi.org/10.1371/journal.pone.0152405
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 John ; 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 S. ; Waxman, Stephen G. ; Patel, Manoj K. ; Butt, Richard P. ; Stevens, Edward B. / Subtype-selective small molecule inhibitors reveal a fundamental role for Nav1.7 in nociceptor electrogenesis, axonal conduction and presynaptic release. In: PLoS ONE. 2016 ; Vol. 11, No. 4.
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title = "Subtype-selective small molecule inhibitors reveal a fundamental role for Nav1.7 in nociceptor electrogenesis, axonal conduction and presynaptic release",
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.",
author = "Alexandrou, {Aristos J.} and Brown, {Adam R.} and Chapman, {Mark L.} and Mark Estacion and Jamie Turner and Mis, {Malgorzata A.} and Anna Wilbrey and Payne, {Elizabeth C.} and Alex Gutteridge and Cox, {Peter John} and Rachel Doyle and David Printzenhoff and Zhixin Lin and Marron, {Brian E.} and Christopher West and Swain, {Nigel A.} and Storer, {R. Ian} and Stupple, {Paul A.} and Castle, {Neil A.} and Hounshell, {James A.} and Mirko Rivara and Andrew Randall and Dib-Hajj, {Sulayman D.} and Krafte, {Douglas S.} and Waxman, {Stephen G.} and Patel, {Manoj K.} and Butt, {Richard P.} and Stevens, {Edward B.}",
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Alexandrou, AJ, Brown, AR, Chapman, ML, Estacion, M, Turner, J, Mis, MA, Wilbrey, A, Payne, EC, Gutteridge, A, Cox, PJ, Doyle, R, Printzenhoff, D, Lin, Z, Marron, BE, West, C, Swain, NA, Storer, RI, Stupple, PA, Castle, NA, Hounshell, JA, Rivara, M, Randall, A, Dib-Hajj, SD, Krafte, DS, Waxman, SG, Patel, MK, Butt, RP & Stevens, EB 2016, 'Subtype-selective small molecule inhibitors reveal a fundamental role for Nav1.7 in nociceptor electrogenesis, axonal conduction and presynaptic release', PLoS ONE, vol. 11, no. 4, e0152405. https://doi.org/10.1371/journal.pone.0152405

Subtype-selective small molecule inhibitors reveal a fundamental role for Nav1.7 in nociceptor electrogenesis, axonal conduction and presynaptic release. / 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 John; 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 S.; Waxman, Stephen G.; Patel, Manoj K.; Butt, Richard P.; Stevens, Edward B.

In: PLoS ONE, Vol. 11, No. 4, e0152405, 01.04.2016.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Subtype-selective small molecule inhibitors reveal a fundamental role for Nav1.7 in nociceptor electrogenesis, axonal conduction and presynaptic release

AU - Alexandrou, Aristos J.

AU - Brown, Adam R.

AU - Chapman, Mark L.

AU - Estacion, Mark

AU - Turner, Jamie

AU - Mis, Malgorzata A.

AU - Wilbrey, Anna

AU - Payne, Elizabeth C.

AU - Gutteridge, Alex

AU - Cox, Peter John

AU - Doyle, Rachel

AU - Printzenhoff, David

AU - Lin, Zhixin

AU - Marron, Brian E.

AU - West, Christopher

AU - Swain, Nigel A.

AU - Storer, R. Ian

AU - Stupple, Paul A.

AU - Castle, Neil A.

AU - Hounshell, James A.

AU - Rivara, Mirko

AU - Randall, Andrew

AU - Dib-Hajj, Sulayman D.

AU - Krafte, Douglas S.

AU - Waxman, Stephen G.

AU - Patel, Manoj K.

AU - Butt, Richard P.

AU - Stevens, Edward B.

PY - 2016/4/1

Y1 - 2016/4/1

N2 - 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.

AB - 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.

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