Protein kinase A regulates inflammatory pain sensitization by modulating HCN2 channel activity in nociceptive sensory neurons

Stefan Herrmann; Hamsa Rajab; Irina Christ; Christoph Schirdewahn; Daniel Höfler; Michael J M Fischer; Ariane Bruno; Stefanie Fenske; Christian Gruner; Felix Kramer; Tassilo Wachsmann; Christian Wahl-Schott; Juliane Stieber; Martin Biel; Andreas Ludwig

doi:10.1097/j.pain.0000000000001005

Protein kinase A regulates inflammatory pain sensitization by modulating HCN2 channel activity in nociceptive sensory neurons

Pain. 2017 Oct;158(10):2012-2024. doi: 10.1097/j.pain.0000000000001005.

Authors

Affiliations

¹ Institut für Experimentelle und Klinische Pharmakologie und Toxikologie, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
² Institut für Physiologie und Pathophysiologie, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
³ Center for Integrated Protein Science Munich CiPS at the Department of Pharmacy-Center for Drug Research, Ludwig-Maximilians-Universität München, München, Germany.

PMID: 28767511
DOI: 10.1097/j.pain.0000000000001005

Abstract

Several studies implicated cyclic adenosine monophosphate (cAMP) as an important second messenger for regulating nociceptor sensitization, but downstream targets of this signaling pathway which contribute to neuronal plasticity are not well understood. We used a Cre/loxP-based strategy to disable the function of either HCN2 or PKA selectively in a subset of peripheral nociceptive neurons and analyzed the nociceptive responses in both transgenic lines. A near-complete lack of sensitization was observed in both mutant strains when peripheral inflammation was induced by an intradermal injection of 8br-cAMP. The lack of HCN2 as well as the inhibition of PKA eliminated the cAMP-mediated increase of calcium transients in dorsal root ganglion neurons. Facilitation of Ih via cAMP, a hallmark of the Ih current, was abolished in neurons without PKA activity. Collectively, these results show a significant contribution of both genes to inflammatory pain and suggest that PKA-dependent activation of HCN2 underlies cAMP-triggered neuronal sensitization.

MeSH terms

8-Bromo Cyclic Adenosine Monophosphate / pharmacology
Animals
Bradykinin / pharmacology
Calcium / metabolism
Cells, Cultured
Cyclic AMP / metabolism
Cyclic AMP-Dependent Protein Kinases / genetics
Cyclic AMP-Dependent Protein Kinases / metabolism*
Ganglia, Spinal / cytology
Hyperalgesia / physiopathology
Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels / genetics
Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels / metabolism*
Inflammation / chemically induced
Mice
Mice, Inbred C57BL
Mice, Transgenic
NAV1.8 Voltage-Gated Sodium Channel / genetics
NAV1.8 Voltage-Gated Sodium Channel / metabolism
Pain Threshold
Phosphorylation / drug effects
Phosphorylation / physiology
Potassium Channels / genetics
Potassium Channels / metabolism*
Proteins / genetics
Proteins / metabolism
Sensory Receptor Cells / drug effects
Sensory Receptor Cells / metabolism*
Signal Transduction

Substances

Hcn2 protein, mouse
Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels
NAV1.8 Voltage-Gated Sodium Channel
Potassium Channels
Proteins
Scn10a protein, mouse
ribonuclease inhibitor protein, mouse
8-Bromo Cyclic Adenosine Monophosphate
Cyclic AMP
Cyclic AMP-Dependent Protein Kinases
Bradykinin
Calcium