PKA-induced internalization of slack KNa channels produces dorsal root ganglion neuron hyperexcitability.
Inflammatory mediators through the activation of the protein kinase A (PKA) pathway sensitize primary afferent nociceptors to mechanical, thermal, and osmotic stimuli. However, it is unclear which ion conductances are responsible for PKA-induced nociceptor hyperexcitability. We have previously shown the abundant expression of Slack sodium-activated potassium (K(Na)) channels in nociceptive dorsal root ganglion (DRG) neurons. Here we show using cultured DRG neurons, that of the total potassium current, I(K), the K(Na) current is predominantly inhibited by PKA. We demonstrate that PKA modulation of K(Na) channels does not happen at the level of channel gating but arises from the internal trafficking of Slack channels from DRG membranes. Furthermore, we found that knocking down the Slack subunit by RNA interference causes a loss of firing accommodation analogous to that observed during PKA activation. Our data suggest that the change in nociceptive firing occurring during inflammation is the result of PKA-induced Slack channel trafficking.
Program in Neuroscience and Department of Pharmacology and Toxicology, The State University of New York at Buffalo, Buffalo, New York 14214, USA.
Megan O
MO
Nuwer
Kelly E
KE
Picchione
Arin
A
Bhattacharjee
D000818:Animals; D019921:Biotinylation; D002478:Cells, Cultured; D017868:Cyclic AMP-Dependent Protein Kinases / Q000235:genetics / Q000494:pharmacology*; D004594:Electrophysiology; D005260:Female; D005727:Ganglia, Spinal / Q000166:cytology / Q000187:drug effects*; D007150:Immunohistochemistry; D008565:Membrane Proteins / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000187:drug effects* / Q000235:genetics; D009474:Neurons / Q000502:physiology*; D009619:Nociceptors / Q000502:physiology; D018408:Patch-Clamp Techniques; D015221:Potassium Channels / Q000187:drug effects* / Q000235:genetics; D000081033:Potassium Channels, Sodium-Activated; D011247:Pregnancy; D034622:RNA Interference; D051381:Rats; D017207:Rats, Sprague-Dawley
D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D015221:Potassium Channels; D000081033:Potassium Channels, Sodium-Activated; C000626167:kcnt1 protein, rat; D017868:Cyclic AMP-Dependent Protein Kinases