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Journal of Neuroinflammation

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Open Access 01-12-2016 | Research

Long-term exposure to PGE₂ causes homologous desensitization of receptor-mediated activation of protein kinase A

Authors: Ramy Habashy Malty, Andy Hudmon, Jill C. Fehrenbacher, Michael R. Vasko

Published in: Journal of Neuroinflammation | Issue 1/2016

Abstract

Background

Acute exposure to prostaglandin E₂ (PGE₂) activates EP receptors in sensory neurons which triggers the cAMP-dependent protein kinase A (PKA) signaling cascade resulting in enhanced excitability of the neurons. With long-term exposure to PGE₂, however, the activation of PKA does not appear to mediate persistent PGE₂-induced sensitization. Consequently, we examined whether homologous desensitization of PGE₂-mediated PKA activation occurs after long-term exposure of isolated sensory neurons to the eicosanoid.

Methods

Sensory neuronal cultures were harvested from the dorsal root ganglia of adult male Sprague-Dawley rats. The cultures were pretreated with vehicle or PGE₂ and used to examine signaling mechanisms mediating acute versus persistent sensitization by exposure to the eicosanoid using enhanced capsaicin-evoked release of immunoreactive calcitonin gene-related peptide (iCGRP) as an endpoint. Neuronal cultures chronically exposed to vehicle or PGE₂ also were used to study the ability of the eicosanoid and other agonists to activate PKA and whether long-term exposure to the prostanoid alters expression of EP receptor subtypes.

Results

Acute exposure to 1 μM PGE₂ augments the capsaicin-evoked release of iCGRP, and this effect is blocked by the PKA inhibitor H-89. After 5 days of exposure to 1 μM PGE₂, administration of the eicosanoid still augments evoked release of iCGRP, but the effect is not attenuated by inhibition of PKA or by inhibition of PI3 kinases. The sensitizing actions of PGE₂ after acute and long-term exposure were attenuated by EP2, EP3, and EP4 receptor antagonists, but not by an EP1 antagonist. Exposing neuronal cultures to 1 μM PGE₂ for 12 h to 5 days blocks the ability of PGE₂ to activate PKA. The offset of the desensitization occurs within 24 h of removal of PGE₂ from the cultures. Long-term exposure to PGE₂ also results in desensitization of the ability of a selective EP4 receptor agonist, L902688 to activate PKA, but does not alter the ability of cholera toxin, forskolin, or a stable analog of prostacyclin to activate PKA.

Conclusions

Long-term exposure to PGE₂ results in homologous desensitization of EP4 receptor activation of PKA, but not to neuronal sensitization suggesting that activation of PKA does not mediate PGE₂-induced sensitization after chronic exposure to the eicosanoid.

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Title: Long-term exposure to PGE2 causes homologous desensitization of receptor-mediated activation of protein kinase A
Authors: Ramy Habashy Malty
Andy Hudmon
Jill C. Fehrenbacher
Michael R. Vasko
Publication date: 01-12-2016
Publisher: BioMed Central
Published in: Journal of Neuroinflammation / Issue 1/2016
Electronic ISSN: 1742-2094
DOI: https://doi.org/10.1186/s12974-016-0645-0

At a glance: The STEP trials

Springer Medicine

Long-term exposure to PGE₂ causes homologous desensitization of receptor-mediated activation of protein kinase A

Abstract

Background

Methods

Results

Conclusions

At a glance: The STEP trials

Springer Medicine

Abstract

Background

Methods

Results

Conclusions

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