In:
Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 106, No. 21 ( 2009-05-26), p. 8725-8730
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.
Type of Medium:
Online Resource
ISSN:
0027-8424
,
1091-6490
DOI:
10.1073/pnas.0901815106
Language:
English
Publisher:
Proceedings of the National Academy of Sciences
Publication Date:
2009
detail.hit.zdb_id:
209104-5
detail.hit.zdb_id:
1461794-8
SSG:
11
SSG:
12
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