GTPgS increases Nav1.8 current in small-diameter dorsal root ganglia neurons
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چکیده
Tetrodotoxin-resistant (TTX-R) sodium current in small-size dorsal root ganglia (DRG) neurons is upregulated by prostaglandin E2 and serotonin through a protein kinase A (PKA)/protein kinase (PKC) pathway, suggesting G protein modulation of one or more TTX-R channels in these neurons. Recently, GTPgS, a hydrolysisresistant analogue of GTP, was shown to increase the persistent current produced by the TTX-R Nav1.9. In this study, we investigated the modulation of another TTX-R channel, Nav1.8, by GTPgS in small-diameter DRG neurons from rats using whole-cell voltage clamp recordings. Because it has been suggested that fluoride, often used in intracellular recording solutions, may bind to trace amounts of aluminum and activate G proteins, we recorded Nav1.8 currents with and without intracellular fluoride, and with the addition of deferoxamine, an aluminum chelator, to prevent fluoride–aluminum binding. Our results show that GTPgS (100 M) caused a significant increase in Nav1.8 current (67%) with a chloride-based intracellular solution. Although the inclusion of fluoride instead of chloride in the pipette solution increased the Nav1.8 current by 177%, GTPgS further increased Nav1.8 current by 67% under these conditions. While the effect of GTPgS was prevented by pretreatment with H7 (100 M), a non-selective PKA/PKC inhibitor, the fluoride-induced increase in Nav1.8 current was not sensitive to H7 (100 M), or to inclusion of deferoxamine (1 mM) in the intracellular solution. We conclude that G protein activation by GTPgS increases Nav1.8 current through a PKA/PKC mechanism and that addition of fluoride to the pipette solution further enhances the current, but is not a confounding variable in the study of Nav1.8 channel modulation by G proteins independent of a PKA/PKC pathway or binding to aluminum.
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تاریخ انتشار 2003