title: 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.
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 SA in a large fraction of DRG neurons and the persistence of this SA long 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. DRG membranes isolated from SCI animals revealed a novel alteration in the regulation of AC. AC activity stimulated by Ca(2+)-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.
  
  
  CONCLUSIONS
  Chronic neuropathic pain is a major clinical problem with poorly understood mechanisms and inadequate treatments. Recent findings indicate that chronic pain in a rat SCI model depends upon hyperactivity in dorsal root ganglia (DRG) neurons. Although cAMP signaling is involved in many forms of neural plasticity, including hypersensitivity of nociceptors in the presence of inflammatory mediators, our finding that continuing cAMP-PKA signaling is required for persistent SA months after SCI and long after isolation of nociceptors is surprising. The dependence of ongoing SA upon AKAP150 and AC5/6 was unknown. The discovery of a dramatic decrease in Gαi inhibition of AC activity after SCI is novel for any physiological system and potentially has broad implications for understanding chronic pain mechanisms.
authors: Departments of Integrative Biology and Pharmacology and.
authors: Alexis
authors: A
authors: Bavencoffe
authors: Departments of Integrative Biology and Pharmacology and.
authors: Yong
authors: Y
authors: Li
authors: Departments of Integrative Biology and Pharmacology and.
authors: Zizhen
authors: Z
authors: Wu
authors: Departments of Integrative Biology and Pharmacology and.
authors: Qing
authors: Q
authors: Yang
authors: Diagnostic and Interventional Imaging, McGovern Medical School at UTHealth, Houston, Texas 77030, and.
authors: Juan
authors: J
authors: Herrera
authors: Department of Pharmaceutical and Biomedical Sciences, College of Pharmacy, University of Georgia, Athens, Georgia 30602.
authors: Eileen J
authors: EJ
authors: Kennedy
authors: Departments of Integrative Biology and Pharmacology and Carmen.W.Dessauer@uth.tmc.edu Edgar.T.Walters@uth.tmc.edu.
authors: Edgar T
authors: http://orcid.org/0000-0003-0718-102X
authors: ET
authors: Walters
authors: Departments of Integrative Biology and Pharmacology and Carmen.W.Dessauer@uth.tmc.edu Edgar.T.Walters@uth.tmc.edu.
authors: Carmen W
authors: http://orcid.org/0000-0003-1210-4280
authors: CW
authors: Dessauer
mesh_terms: D054758:A Kinase Anchor Proteins / Q000494:pharmacology; D000200:Action Potentials / Q000187:drug effects / Q000502:physiology*; D000262:Adenylyl Cyclases / Q000502:physiology*; D000818:Animals; D002478:Cells, Cultured; D017868:Cyclic AMP-Dependent Protein Kinases / Q000502:physiology*; D005727:Ganglia, Spinal / Q000187:drug effects / Q000201:enzymology*; D008297:Male; D009619:Nociceptors / Q000502:physiology*; D051381:Rats; D013119:Spinal Cord Injuries / Q000201:enzymology* / Q000473:pathology; D054457:Tissue Scaffolds
chemical_list: D054758:A Kinase Anchor Proteins; C415703:Akap5 protein, rat; D017868:Cyclic AMP-Dependent Protein Kinases; D000262:Adenylyl Cyclases
keywords: A-kinase anchoring protein; DRG; cAMP; chronic pain; hyperexcitability; spontaneous activity