NF-κB Mediated Enhancement of Potassium Currents by the Chemokine CXCL1/Growth Related Oncogene in Small Diameter Rat Sensory Neurons

Abstract

BackgroundInflammatory processes play important roles in both neuropathic and inflammatory pain states, but the effects of inflammation per se within the sensory ganglia are not well understood. The cytokine growth-related oncogene (GRO/KC; CXCL1) shows strong, rapid upregulation in dorsal root ganglion (DRG) in both nerve injury and inflammatory pain models. We examined the direct effects of GRO/KC on small diameter DRG neurons, which are predominantly nociceptive. Whole cell voltage clamp technique was used to measure voltage-activated potassium (K) currents in acutely cultured adult rat small diameter sensory neurons. Fluorescently labeled isolectin B4 (IB4) was used to classify cells as IB4-positive or IB4-negative.ResultsIn IB4-negative neurons, voltage-activated K current densities of both transient and sustained components were increased after overnight incubation with GRO/KC (1.5 nM), without marked changes in voltage dependence or kinetics. The average values for the slow and fast decay time constants at 20 mV were unchanged by GRO/KC. The amplitude of the fast inactivating component increased significantly with no large shifts in the voltage dependence of inactivation. The increase in K currents was completely blocked by co-incubation with protein synthesis inhibitor cycloheximide (CHX) or NF-κB inhibitors pyrrolidine dithiocarbamate (PDTC) or quinazoline (6-Amino-4-(4-phenoxypheny lethylamino;QNZ). In contrast, the voltage-activated K current of IB4-positive neurons was unchanged by GRO/KC. GRO/KC incubation caused no significant changes in the expression level of eight selected voltage-gated K channel genes in quantitative PCR analysis.ConclusionThe results suggest that GRO/KC has important effects in inflammatory processes via its direct actions on sensory neurons, and that activation of NF-κB is involved in the GRO/KC-induced enhancement of K currents.

Impaired excitability of renal afferent innervation after exposure to the inflammatory chemokine CXCL1

“…The CXCL1 concentration used in our experiments was similar to that used in other studies (43,45). Some investigators used even higher concentrations in the context of chemokine-induced calcitonin gene-related peptide release in DRG (29).…”

“…Of particular interest are A-type voltage-gated potassium currents, the blockade of which reduces firing frequency (42). Interestingly, CXCL1 exposure has been shown to affect the amplitude but not the kinetics of fast inactivating potassium currents by an NF-B-dependent pathway (45).…”

Docosahexaenoic acid inhibits mechanical allodynia and thermal hyperalgesia in diabetic rats by decreasing the excitability of DRG neurons

“…There were about 20% of large neurons that expressed high levels of Nav1.8 and mediated TTX-R Na current (Ho and O'Leary, 2011;Lai et al, 2003) Although we did not exclude the small cells when performing the RT-PCR and Western blot detection, according to the results from patch-clamp recording, we proposed that both Nav1.3 and 1.7 contributed to the increase of TTX-S Na currents and Nav1.8 was the main contributor of TTX-R Na current of medium DRG neurons in STZ-induced diabetic rats. Potassium currents, including slowly inactivating 'sustained' currents (IK) and rapidly inactivating 'transient' A-type currents (IA), have important roles in modulating neuronal excitability (Gold et al, 1996;Yang et al, 2009). It has been reported that Atype K channels contributed to the excitability of DRG neurons and played a role in diabetic neuropathy (Cao et al, 2010;Sun et al, 2012b).…”

Chemokine CXCL1 enhances inflammatory pain and increases NMDA receptor activity and COX-2 expression in spinal cord neurons via activation of CXCR2

“…In addition, CXCL1 increases the sodium currents, potassium currents in small diameter rat sensory neurons (Dong et al, 2012; Wang et al, 2008; Yang et al, 2009). Intrathecal injection of CXCL1 induced CXCR2-dependent heat hyperalgesia (Zhang et al, 2013).…”