Role of receptor protein tyrosine phosphatase alpha (RPTPalpha) and tyrosine phosphorylation in the serotonergic inhibition of voltage-dependent potassium channels.
The activity of voltage-gated potassium (Kv) channels can be dynamically modulated by several events, including neurotransmitter-stimulated biochemical cascades mediated by G-protein-coupled receptors. By using a heterologous expression system, we show that activating the 5-HT2C receptor inhibits both Kv1.1 and Kv1.2 channels through a tyrosine phosphorylation mechanism. The major molecular determinants of channel inhibition were identified as two tyrosine residues located in the N-terminal region of the Kv channel subunit. Furthermore, we demonstrate that receptor protein tyrosine phosphatase alpha (RPTPalpha), a receptor protein tyrosine phosphatase, co-ordinates the inhibition process mediated via 5-HT2C receptors. We therefore propose that the serotonergic regulation of human Kv1.1 and Kv1.2 channel activity by the 5-HT2C receptor involves the dual coordination of both RPTPalpha and specific tyrosine kinases coupled to this receptor.
Imbrici
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Istituto di Ricerche Farmacologiche Mario Negri, Consorzio Mario Negri Sud, Department of Vascular Medicine and Pharmacology, Chieti, Italy.
Tucker
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SJ
D'Adamo
M C
MC
Pessia
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D000818:Animals; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D015870:Gene Expression; D019833:Genistein / Q000494:pharmacology; D006801:Humans; D007700:Kinetics; D051662:Kv1.1 Potassium Channel; D051663:Kv1.2 Potassium Channel; D016297:Mutagenesis, Site-Directed; D009865:Oocytes / Q000378:metabolism; D010766:Phosphorylation; D019000:Phosphotyrosine / Q000378:metabolism*; D026902:Potassium Channel Blockers; D015221:Potassium Channels / Q000235:genetics / Q000502:physiology; D024642:Potassium Channels, Voltage-Gated; D017027:Protein Tyrosine Phosphatases / Q000502:physiology*; D054630:Receptor-Like Protein Tyrosine Phosphatases, Class 4; D011956:Receptors, Cell Surface; D011985:Receptors, Serotonin / Q000235:genetics / Q000502:physiology; D012701:Serotonin / Q000502:physiology*; D014162:Transfection; D014638:Vanadates / Q000494:pharmacology; D014982:Xenopus laevis
D004791:Enzyme Inhibitors; C496946:KCNA1 protein, human; C496969:KCNA2 protein, human; D051663:Kv1.2 Potassium Channel; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated; D011956:Receptors, Cell Surface; D011985:Receptors, Serotonin; D051662:Kv1.1 Potassium Channel; D019000:Phosphotyrosine; D012701:Serotonin; D014638:Vanadates; D019833:Genistein; C516841:PTPRA protein, human; D017027:Protein Tyrosine Phosphatases; D054630:Receptor-Like Protein Tyrosine Phosphatases, Class 4