• Br. J. Pharmacol. · Feb 2013

    AKAP-dependent sensitization of Ca(v) 3.2 channels via the EP(4) receptor/cAMP pathway mediates PGE(2) -induced mechanical hyperalgesia.

    • Fumiko Sekiguchi, Yuka Aoki, Maiko Nakagawa, Daiki Kanaoka, Yuta Nishimoto, Maho Tsubota-Matsunami, Rumi Yamanaka, Shigeru Yoshida, and Atsufumi Kawabata.
    • Division of Pharmacology & Pathophysiology, Kinki University School of Pharmacy, Higashi-Osaka, Japan.
    • Br. J. Pharmacol. 2013 Feb 1; 168 (3): 734-45.

    Background And PurposeThe Ca(v) 3.2 isoform of T-type Ca(2+) channels (T channels) is sensitized by hydrogen sulfide, a pro-nociceptive gasotransmitter, and also by PKA that mediates PGE(2) -induced hyperalgesia. Here we examined and analysed Ca(v) 3.2 sensitization via the PGE(2) /cAMP pathway in NG108-15 cells that express Ca(v) 3.2 and produce cAMP in response to PGE(2) , and its impact on mechanical nociceptive processing in rats.Experimental ApproachIn NG108-15 cells and rat dorsal root ganglion (DRG) neurons, T-channel-dependent currents (T currents) were measured with the whole-cell patch-clamp technique. The molecular interaction of Ca(v) 3.2 with A-kinase anchoring protein 150 (AKAP150) and its phosphorylation were analysed by immunoprecipitation/immunoblotting in NG108-15 cells. Mechanical nociceptive threshold was determined by the paw pressure test in rats.Key ResultsIn NG108-15 cells and/or rat DRG neurons, dibutyryl cAMP (db-cAMP) or PGE(2) increased T currents, an effect blocked by AKAP St-Ht31 inhibitor peptide (AKAPI) or KT5720, a PKA inhibitor. The effect of PGE(2) was abolished by RQ-00015986-00, an EP(4) receptor antagonist. AKAP150 was co-immunoprecipitated with Ca(v) 3.2, regardless of stimulation with db-cAMP, and Ca(v) 3.2 was phosphorylated by db-cAMP or PGE(2) . In rats, intraplantar (i.pl.) administration of db-cAMP or PGE(2) caused mechanical hyperalgesia, an effect suppressed by AKAPI, two distinct T-channel blockers, NNC 55-0396 and ethosuximide, or ZnCl(2) , known to inhibit Ca(v) 3.2 among T channels. Oral administration of RQ-00015986-00 suppressed the PGE(2) -induced mechanical hyperalgesia.Conclusion And ImplicationsOur findings suggest that PGE(2) causes AKAP-dependent phosphorylation and sensitization of Ca(v) 3.2 through the EP(4) receptor/cAMP/PKA pathway, leading to mechanical hyperalgesia in rats.© 2012 The Authors. British Journal of Pharmacology © 2012 The British Pharmacological Society.

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