Persistent electrical activity in primary nociceptors after spinal cord injury is maintained by scaffolded adenylyl cyclase and protein kinase A and is associated with altered adenylyl cyclase regulation

Alexis Bavencoffe, Yong Li, Zizhen Wu, Qing Yang, Juan Herrera, Eileen J. Kennedy, Edgar T. Walters, Carmen W. Dessauer

Research output: Contribution to journalArticle

21 Scopus citations

Abstract

Little is known about intracellular signaling mechanisms that persistently excite neurons in pain pathways. Persistent spontaneous activity (SA) generated in the cell bodies of primary nociceptors within dorsal root ganglia (DRG) has been found to make major contributions to chronic pain in a rat model of spinal cord injury (SCI) (Bedi et al., 2010; Yang et al., 2014). The occurrence of SCI-induced SAin a large fraction ofDRGneurons and the persistence of thisSAlong after dissociation of the neurons provide an opportunity to define intrinsic cell signaling mechanisms that chronically drive SA in pain pathways. The present study demonstrates that SCI-induced SA requires continuing activity of adenylyl cyclase (AC) and cAMP-dependent protein kinase (PKA), as well as a scaffolded complex containing AC5/6, A-kinase anchoring protein 150 (AKAP150), and PKA. SCI caused a small but significant increase in the expression of AKAP150 but not other AKAPs.DRGmembranes isolated from SCI animals revealed a novel alteration in the regulation of AC.ACactivity stimulated by Ca2+-calmodulin increased, while the inhibition of AC activity by Gαi showed an unexpected and dramatic decrease after SCI. Localized enhancement of the activity of AC within scaffolded complexes containing PKA is likely to contribute to chronic pathophysiological consequences of SCI, including pain, that are promoted by persistent hyperactivity in DRG neurons.

Original languageEnglish (US)
Pages (from-to)1660-1668
Number of pages9
JournalJournal of Neuroscience
Volume36
Issue number5
DOIs
StatePublished - Feb 3 2016
Externally publishedYes

Keywords

  • A-kinase anchoring protein
  • CAMP
  • Chronic pain
  • DRG
  • Hyperexcitability
  • Spontaneous activity

ASJC Scopus subject areas

  • Neuroscience(all)

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