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The Journal of Neuroscience, June 29, 2005, 25(26):6119-6126; doi:10.1523/JNEUROSCI.0285-05.2005

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Cellular/Molecular
Epac Mediates a cAMP-to-PKC Signaling in Inflammatory Pain: An Isolectin B4(+) Neuron-Specific Mechanism

Tim B. Hucho, Olayinka A. Dina, and Jon D. Levine

National Institutes of Health Pain Center, University of California, San Francisco, San Francisco, California 94143

The isoform of protein kinase C (PKC) has emerged as a critical second messenger in sensitization toward mechanical stimulation in models of neuropathic (diabetes, alcoholism, and cancer therapy) as well as acute and chronic inflammatory pain. Signaling pathways leading to activation of PKC remain unknown. Recent results indicate signaling from cAMP to PKC. A mechanism connecting cAMP and PKC, two ubiquitous, commonly considered separate pathways, remains elusive. We found that, in cultured DRG neurons, signaling from cAMP to PKC is not mediated by PKA but by the recently identified cAMP-activated guanine exchange factor Epac. Epac, in turn, was upstream of phospholipase C (PLC) and PLD, both of which were necessary for translocation and activation of PKC. This signaling pathway was specific to isolectin B4-positive [IB4(+)] nociceptors. Also, in a behavioral model, cAMP produced mechanical hyperalgesia (tenderness) through Epac, PLC/PLD, and PKC. By delineating this signaling pathway, we provide a mechanism for cAMP-to-PKC signaling, give proof of principle that the mitogen-activated protein kinase pathway-activating protein Epac also stimulates PKC, describe the first physiological function unique for the IB4(+) subpopulation of sensory neurons, and find proof of principle that G-protein-coupled receptors can activate PKC not only through the G-proteins _q and but also through _s.

Key words: nociception; inflammation; intracellular signaling; -adrenergic receptor; cAMP; PKC; Epac; PLD; IB4

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Received Jan 20, 2005; revised May 8, 2005; accepted May 9, 2005.

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