Details

Autor(en) / Beteiligte

• Belkouch, Mounir
• Dansereau, Marc-André
• Réaux-Le Goazigo, Annabelle
• Van Steenwinckel, Juliette
• Beaudet, Nicolas
• Chraibi, Ahmed
• Melik-Parsadaniantz, Stéphane
• Sarret, Philippe

Titel

The Chemokine CCL2 Increases Na v 1.8 Sodium Channel Activity in Primary Sensory Neurons through a Gβγ-Dependent Mechanism

Ist Teil von

• The Journal of neuroscience, 2011-12, Vol.31 (50), p.18381-18390

Erscheinungsjahr

2011

Quelle

EZB Electronic Journals Library

Beschreibungen/Notizen

• Changes in function of voltage-gated sodium channels in nociceptive primary sensory neurons participate in the development of peripheral hyperexcitability that occurs in neuropathic and inflammatory chronic pain conditions. Among them, the tetrodotoxin-resistant (TTX-R) sodium channel Na v 1.8, primarily expressed by small- and medium-sized dorsal root ganglion (DRG) neurons, substantially contributes to the upstroke of action potential in these neurons. Compelling evidence also revealed that the chemokine CCL2 plays a critical role in chronic pain facilitation via its binding to CCR2 receptors. In this study, we therefore investigated the effects of CCL2 on the density and kinetic properties of TTX-R Na v 1.8 currents in acutely small/medium dissociated lumbar DRG neurons from naive adult rats. Whole-cell patch-clamp recordings demonstrated that CCL2 concentration-dependently increased TTX-resistant Na v 1.8 current densities in both small- and medium-diameter sensory neurons. Incubation with CCL2 also shifted the activation and steady-state inactivation curves of Na v 1.8 in a hyperpolarizing direction in small sensory neurons. No change in the activation and inactivation kinetics was, however, observed in medium-sized nociceptive neurons. Our electrophysiological recordings also demonstrated that the selective CCR2 antagonist INCB3344 [ N -[2-[[(3 S ,4 S )-1- E 4-(1,3-benzodioxol-5-yl)-4-hydroxycyclohexyl]-4-ethoxy-3-pyrrolidinyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide] blocks the potentiation of Na v 1.8 currents by CCL2 in a concentration-dependent manner. Furthermore, the enhancement in Na v 1.8 currents was prevented by pretreatment with pertussis toxin (PTX) or gallein (a Gβγ inhibitor), indicating the involvement of Gβγ released from PTX-sensitive G i/o -proteins in the cross talk between CCR2 and Na v 1.8. Together, our data clearly demonstrate that CCL2 may excite primary sensory neurons by acting on the biophysical properties of Na v 1.8 currents via a CCR2/Gβγ-dependent mechanism.