cAMP signaling through protein kinase A and Epac2 induces substance P release in the rat spinal cord
| Autor: | Helena S. Ennes, Wenling Chen, James A. McRoberts, Juan Carlos G. Marvizón |
|---|---|
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Male TRPV1 Substance P Pharmacology Article Adenylyl cyclase Rats Sprague-Dawley 03 medical and health sciences Cellular and Molecular Neuroscience chemistry.chemical_compound 0302 clinical medicine Organ Culture Techniques Tachykinin receptor 1 Cyclic AMP Animals Guanine Nucleotide Exchange Factors Protein kinase A Cells Cultured Forskolin Voltage-dependent calcium channel Colforsin Cyclic AMP-Dependent Protein Kinases Rats Posterior Horn Cells 030104 developmental biology chemistry nervous system Spinal Cord Hyperalgesia NMDA receptor 030217 neurology & neurosurgery Signal Transduction |
| Zdroj: | Neuropharmacology |
| ISSN: | 1873-7064 |
| Popis: | Using neurokinin 1 receptor (NK1R) internalization to measure of substance P release in rat spinal cord slices, we found that it was induced by the adenylyl cyclase (AC) activator forskolin, by the protein kinase A (PKA) activators 6-Bnz-cAMP and 8-Br-cAMP, and by the activator of exchange protein activated by cAMP (Epac) 8-pCPT-2-O-Me-cAMP (CPTOMe-cAMP). Conversely, AC and PKA inhibitors decreased substance P release induced by electrical stimulation of the dorsal root. Therefore, the cAMP signaling pathway mediates substance P release in the dorsal horn. The effects of forskolin and 6-Bnz-cAMP were not additive with NMDA-induced substance P release and were decreased by the NMDA receptor blocker MK-801. In cultured dorsal horn neurons, forskolin increased NMDA-induced Ca(2+) entry and the phosphorylation of the NR1 and NR2B subunits of the NMDA receptor. Therefore, cAMP-induced substance P release is mediated by the activating phosphorylation by PKA of NMDA receptors. Voltage-gated Ca(2+) channels, but not by TRPV1 or TRPA1, also contributed to cAMP-induced substance P release. Activation of PKA was required for the effects of forskolin and the three cAMP analogs. Epac2 contributed to the effects of forskolin and CPTOMe-cAMP, signaling through a Raf - mitogen-activated protein kinase pathway to activate Ca(2+) channels. Epac1 inhibitors induced NK1R internalization independently of substance P release. In rats with latent sensitization to pain, the effect of 6-Bnz-cAMP was unchanged, whereas the effect of forskolin was decreased due to the loss of the stimulatory effect of Epac2. Hence, substance P release induced by cAMP decreases during pain hypersensitivity. |
| Databáze: | OpenAIRE |
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