Reduced excitability of gp130-deficient nociceptors is associated with increased voltage-gated potassium currents and Kcna4 channel upregulation.
Neuropathic pain and pain arising from local inflammation are characterized by increased release of inflammatory mediators like interleukin-6 (IL-6) by immune cells. The levels of IL-6 is increased in various painfull conditions and correlates with the severity of thermal and mechanical hypersensitivity. Deletion of the IL-6 signal transducer glycoprotein 130 (gp130) reduces inflammation associated with hypersensitivity to thermal and mechanical stimuli. In this study, we show that nociceptor-specific deletion of gp130 alters excitability parameters that are linked to changes in the potassium conductance. In SNS-gp130(-/-) sensory neurons, the resting membrane potential was reduced. Moreover the repolarization speed of the action potential and afterhypolarization was augmented, however, voltage-gated Na(+) and Ca(2+) current were not obviously altered. The main difference between gp130-deficient and control neurons was a significant increase in the conductance of both delayed rectifier as well as A-type potassium currents. Taqman RT-PCR analysis revealed significantly higher levels of Kcna4 mRNA, encoding A-type Kv1.4 potassium channel, in neuron cultures from SNS-gp130(-/-) versus control mice, which may account for the electrophysiological data. No difference in other voltage-gated ion channel mRNAs was observed. The present data show for the first time increased A-type K(+) currents and expression of voltage-gated potassium channel Kcna4 (Kv1.4) in SNS-gp130(-/-) nociceptors. This suggests that gp130 acts as a break for the expression of potassium channels and important regulator hub for nociceptor excitability.
Department of Physiology and Biomedical Physics, Division of Physiology, Medical University of Innsbruck, Fritz-Pregl Strasse 3-I, A-6020, Innsbruck, Austria, michiel.langeslag@i-med.ac.at.
Michiel
M
Langeslag
Philipp
P
Malsch
Andrea
A
Welling
Michaela
M
Kress
D000818:Animals; D002118:Calcium / Q000378:metabolism; D006023:Glycoproteins / Q000172:deficiency* / Q000235:genetics; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism; D051665:Kv1.4 Potassium Channel / Q000235:genetics / Q000378:metabolism*; D008564:Membrane Potentials / Q000235:genetics / Q000502:physiology; D051379:Mice; D009619:Nociceptors / Q000378:metabolism*; D011188:Potassium / Q000378:metabolism; D024642:Potassium Channels, Voltage-Gated / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D011984:Sensory Receptor Cells / Q000378:metabolism / Q000502:physiology; D012964:Sodium / Q000378:metabolism; D015854:Up-Regulation
D006023:Glycoproteins; D015850:Interleukin-6; C496978:Kcna4 protein, mouse; D051665:Kv1.4 Potassium Channel; D024642:Potassium Channels, Voltage-Gated; D012333:RNA, Messenger; D012964:Sodium; D011188:Potassium; D002118:Calcium