Suppressed Ca2+/CaM/CaMKII-dependent KATP channel activity in primary afferent neurons mediates hyperalgesia after axotomy

Takashi Kawano, Vasiliki Zoga, Geza Gemes, J. Bruce McCallum, Hsiang En Wu, Danijel Pravdic, Mei Ying Liang, Wai Meng Kwok, Quinn Hogan, Constantine Sarantopoulos

Research output: Contribution to journalArticlepeer-review

51 Scopus citations

Abstract

Painful axotomy decreases KATP channel current (IK ATP) in primary afferent neurons. Because cytosolic Ca2+ signaling is depressed in injured dorsal root ganglia (DRG) neurons, we investigated whether Ca2+-calmodulin (CaM)-Ca2+/CaM- dependent kinase II (CaMKII) regulates IKATP in large DRG neurons. Immunohistochemistry identified the presence of KATP channel subunits SUR1, SUR2, and Kir6.2 but not Kir6.1, and pCaMKII in neurofilament 200-positive DRG somata. Single-channel recordings from cell-attached patches revealed that basal and evoked IKATP by ionomycin, a Ca2+ ionophore, is activated by CaMKII. In axotomized neurons from rats made hyperalgesic by spinal nerve ligation (SNL), basal KATP channel activity was decreased, and sensitivity to ionomycin was abolished. Basal and Ca2+-evoked KATP channel activity correlated inversely with the degree of hyperalgesia induced by SNL in the rats from which the neurons were isolated. Inhibition of IKATP by glybenclamide, a selective KATP channel inhibitor, depolarized resting membrane potential (RMP) recorded in perforated whole-cell patches and enhanced neurotransmitter release measured by amperometry. The selective KATP channel opener diazoxide hyperpolarized the RMP and attenuated neurotransmitter release. Axotomized neurons from rats made hyperalgesic by SNL lost sensitivity to the myristoylated form of autocamtide-2-related inhibitory peptide (AIPm), a pseudosubstrate blocker of CaMKII, whereas axotomized neurons from SNL animals that failed to develop hyperalgesia showed normal IKATP inhibition by AIPm. AIPm also depolarized RMP in control neurons via KATP channel inhibition. Unitary current conductance and sensitivity of KATP channels to cytosolic ATP and ligands were preserved even after painful nerve injury, thus providing opportunities for selective therapeutic targeting against neuropathic pain.

Original languageEnglish (US)
Pages (from-to)8725-8730
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume106
Issue number21
DOIs
StatePublished - May 26 2009
Externally publishedYes

Keywords

  • Calcium
  • Calmodulin
  • Dorsal root ganglia
  • Neuropathic pain
  • Potassium channels

ASJC Scopus subject areas

  • General

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