| Mechanism of sodium channel NaV1.9 potentiation by G-protein signaling. | |
| | |
MedLine Citation:
|
PMID: 23359282 Owner: NLM Status: In-Data-Review |
Abstract/OtherAbstract:
|
Tetrodotoxin (TTX)-resistant voltage-gated Na (Na(V)) channels have been implicated in nociception. In particular, Na(V)1.9 contributes to expression of persistent Na current in small diameter, nociceptive sensory neurons in dorsal root ganglia and is required for inflammatory pain sensation. Using ND7/23 cells stably expressing human Na(V)1.9, we elucidated the biophysical mechanisms responsible for potentiation of channel activity by G-protein signaling to better understand the response to inflammatory mediators. Heterologous Na(V)1.9 expression evoked TTX-resistant Na current with peak activation at -40 mV with extensive overlap in voltage dependence of activation and inactivation. Inactivation kinetics were slow and incomplete, giving rise to large persistent Na currents. Single-channel recording demonstrated long openings and correspondingly high open probability (P(o)) accounting for the large persistent current amplitude. Channels exposed to intracellular GTPγS, a proxy for G-protein signaling, exhibited twofold greater current density, slowing of inactivation, and a depolarizing shift in voltage dependence of inactivation but no change in activation voltage dependence. At the single-channel level, intracellular GTPγS had no effect on single-channel amplitude but caused an increased mean open time and greater P(o) compared with recordings made in the absence of GTPγS. We conclude that G-protein activation potentiates human Na(V)1.9 activity by increasing channel open probability and mean open time, causing the larger peak and persistent current, respectively. Our results advance our understanding about the mechanism of Na(V)1.9 potentiation by G-protein signaling during inflammation and provide a cellular platform useful for the discovery of Na(V)1.9 modulators with potential utility in treating inflammatory pain. |
| | |
Authors:
|
Carlos G Vanoye; Jennifer D Kunic; George R Ehring; Alfred L George |
Publication Detail:
|
Type: Journal Article |
Journal Detail:
|
Title: The Journal of general physiology Volume: 141 ISSN: 1540-7748 ISO Abbreviation: J. Gen. Physiol. Publication Date: 2013 Feb |
Date Detail:
|
Created Date: 2013-01-29 Completed Date: - Revised Date: - |
Medline Journal Info:
|
Nlm Unique ID: 2985110R Medline TA: J Gen Physiol Country: United States |
Other Details:
|
Languages: eng Pagination: 193-202 Citation Subset: IM |
Affiliation:
|
Department of Medicine and 2 Department of Pharmacology, Vanderbilt University, Nashville, TN 37232. |
Export Citation:
|
APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
|
|
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
Previous Document: Ca2+ oscillations, Ca2+ sensitization, and contraction activated by protein kinase C in small airway...
Next Document: Opening the Shaker K+ channel with hanatoxin.