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The Journal of Neuroscience, May 15, 1999, 19(10):3739-3751

Roles of G-Protein , Arachidonic Acid, and Phosphorylation in Convergent Activation of an S-Like Potassium Conductance by Dopamine, Ala-Pro-Gly-Trp-NH₂, and Phe-Met-Arg-Phe-NH₂

Hind van Tol-Steye^{1, 2}, Johannes C. Lodder¹, Huibert D. Mansvelder¹, Rudi J. Planta², Harm van Heerikhuizen², and Karel S. Kits¹

Departments of ¹ Neurophysiology, Research Institute Neurosciences, and ² Biochemistry and Molecular Biology, Faculty of Chemistry, Vrije Universiteit, 1081 HV Amsterdam, The Netherlands

Dopamine and the neuropeptides Ala-Pro-Gly-Trp-NH₂ (APGWamide or APGWa) and Phe-Met-Arg-Phe-NH₂ (FMRFamide or FMRFa) all activate an S-like potassium channel in the light green cells of the mollusc Lymnaea stagnalis, neuroendocrine cells that release insulin-related peptides. We studied the signaling pathways underlying the responses, the role of the G-protein subunit, and the interference by phosphorylation pathways. All responses are blocked by an inhibitor of arachidonic acid (AA) release, 4-bromophenacylbromide, and by inhibitors of lipoxygenases (nordihydroguaiaretic acid and AA-861) but not by indomethacin, a cyclooxygenase inhibitor. AA and phospholipase A₂ (PLA₂) induced currents with similar I-V characteristics and potassium selectivity as dopamine, APGWa, and FMRFa. PLA₂ occluded the response to FMRFa. We conclude that convergence of the actions of dopamine, APGWa, and FMRFa onto the S-like channel occurs at or upstream of the level of AA and that formation of lipoxygenase metabolites of AA is necessary to activate the channel. Injection of a synthetic peptide, which interferes with G-protein subunits, inhibited the agonist-induced potassium current. This suggests that subunits mediate the response, possibly by directly coupling to a phospholipase. Finally, the responses to dopamine, APGWa, and FMRFa were inhibited by activation of PKA and PKC, suggesting that the responses are counteracted by PKA- and PKC-dependent phosphorylation. The PLA₂-activated potassium current was inhibited by 8-chlorophenylthio-cAMP but not by 12-O-tetradecanoylphorbol 13-acetate (TPA). However, TPA did inhibit the potassium current induced by irreversible activation of the G-protein using GTP--S. Thus, it appears that PKA targets a site downstream of AA formation, e.g., the potassium channel, whereas PKC acts at the active G-protein or the phospholipase.

Key words: FMRFamide; dopamine; neuropeptide; K⁺-current; S-current; molluscs; arachidonic acid; G-protein subunits; neuron; signal transduction; convergence

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Copyright © 1999 Society for Neuroscience  0270-6474/99/19103739-13$05.00/0

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