title: The chemokine CCL2 increases Nav1.8 sodium channel activity in primary sensory neurons through a Gβγ-dependent mechanism.
abstract: 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-[[(3S,4S)-1-E4-(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.
authors.affiliation: Department of Physiology and Biophysics, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, Quebec J1H 5N4, Canada.
authors.forename: Mounir
authors.initials: M
authors.lastname: Belkouch
authors.forename: Marc-André
authors.initials: MA
authors.lastname: Dansereau
authors.forename: Annabelle
authors.initials: A
authors.lastname: Réaux-Le Goazigo
authors.forename: Juliette
authors.initials: J
authors.lastname: Van Steenwinckel
authors.forename: Nicolas
authors.initials: N
authors.lastname: Beaudet
authors.forename: Ahmed
authors.initials: A
authors.lastname: Chraibi
authors.forename: Stéphane
authors.initials: S
authors.lastname: Melik-Parsadaniantz
authors.forename: Philippe
authors.initials: P
authors.lastname: Sarret
mesh_terms: D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D000818:Animals; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000378:metabolism / Q000494:pharmacology*; D044387:GTP-Binding Protein beta Subunits / Q000378:metabolism*; D005727:Ganglia, Spinal / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D062559:NAV1.8 Voltage-Gated Sodium Channel; D018408:Patch-Clamp Techniques; D051381:Rats; D017207:Rats, Sprague-Dawley; D011984:Sensory Receptor Cells / Q000187:drug effects / Q000378:metabolism*; D015222:Sodium Channels / Q000378:metabolism*
chemical_list: D018932:Chemokine CCL2; D044387:GTP-Binding Protein beta Subunits; D062559:NAV1.8 Voltage-Gated Sodium Channel; C568319:Scn10a protein, rat; D015222:Sodium Channels