Faculty Collaboration Database

Suppressed Ca2+/CaM/CaMKII-dependent K(ATP) channel activity in primary afferent neurons mediates hyperalgesia after axotomy. Proc Natl Acad Sci U S A 2009 May 26;106(21):8725-30

Date

05/15/2009

Pubmed ID

19439665

Pubmed Central ID

PMC2681318

DOI

10.1073/pnas.0901815106

Scopus ID

2-s2.0-66649097000 (requires institutional sign-in at Scopus site)   60 Citations

Abstract

Painful axotomy decreases K(ATP) channel current (IK(ATP)) in primary afferent neurons. Because cytosolic Ca(2+) signaling is depressed in injured dorsal root ganglia (DRG) neurons, we investigated whether Ca(2+)-calmodulin (CaM)-Ca(2+)/CaM-dependent kinase II (CaMKII) regulates IK(ATP) in large DRG neurons. Immunohistochemistry identified the presence of K(ATP) 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 IK(ATP) by ionomycin, a Ca(2+) ionophore, is activated by CaMKII. In axotomized neurons from rats made hyperalgesic by spinal nerve ligation (SNL), basal K(ATP) channel activity was decreased, and sensitivity to ionomycin was abolished. Basal and Ca(2+)-evoked K(ATP) channel activity correlated inversely with the degree of hyperalgesia induced by SNL in the rats from which the neurons were isolated. Inhibition of IK(ATP) by glybenclamide, a selective K(ATP) channel inhibitor, depolarized resting membrane potential (RMP) recorded in perforated whole-cell patches and enhanced neurotransmitter release measured by amperometry. The selective K(ATP) 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 IK(ATP) inhibition by AIPm. AIPm also depolarized RMP in control neurons via K(ATP) channel inhibition. Unitary current conductance and sensitivity of K(ATP) channels to cytosolic ATP and ligands were preserved even after painful nerve injury, thus providing opportunities for selective therapeutic targeting against neuropathic pain.

Author List

Kawano T, Zoga V, Gemes G, McCallum JB, Wu HE, Pravdic D, Liang MY, Kwok WM, Hogan Q, Sarantopoulos C

Author

Wai-Meng Kwok PhD Professor in the Anesthesiology department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Animals
Axotomy
Calcium
Calcium-Calmodulin-Dependent Protein Kinase Type 2
Calmodulin
Cell-Free System
Electrophysiological Phenomena
Ganglia, Spinal
Hyperalgesia
Ionomycin
KATP Channels
Male
Neurons, Afferent
Patch-Clamp Techniques
Rats
Rats, Sprague-Dawley