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| Content Provider | World Health Organization (WHO)-Global Index Medicus |
|---|---|
| Author | Shi, Yun Cui, Ningren Jiang, Chun Shi, Weiwei |
| Description | Author Affiliation: Shi Y ( Department of Biology, Georgia State University, 33 Gilmer Street, Atlanta, GA 30302-4010, USA.) |
| Abstract | Vascular ATP-sensitive K(+) channels are inhibited by multiple vasoconstricting hormones via the protein kinase C (PKC) pathway. However, the molecular substrates for PKC phosphorylation remain unknown. To identify the PKC sites, Kir6.1/SUR2B and Kir6.2/SUR2B were expressed in HEK293 cells. Following channel activation by pinacidil, the catalytic fragment of PKC inhibited the Kir6.1/SUR2B currents but not the Kir6.2/SUR2B currents. Phorbol 12-myristate 13-acetate (a PKC activator) had similar effects. Using Kir6.1-Kir6.2 chimeras, two critical protein domains for the PKC-dependent channel inhibition were identified. The proximal N terminus of Kir6.1 was necessary for channel inhibition. Because there was no PKC phosphorylation site in the N-terminal region, our results suggest its potential involvement in channel gating. The distal C terminus of Kir6.1 was crucial where there are several consensus PKC sites. Mutation of Ser-354, Ser-379, Ser-385, Ser-391, or Ser-397 to nonphosphorylatable alanine reduced PKC inhibition moderately but significantly. Combined mutations of these residues had greater effects. The channel inhibition was almost completely abolished when 5 of them were jointly mutated. In vitro phosphorylation assay showed that 4 of the serine residues were necessary for the PKC-dependent (32)P incorporation into the distal C-terminal peptides. Thus, a motif containing four phosphorylation repeats is identified in the Kir6.1 subunit underlying the PKC-dependent inhibition of the Kir6.1/SUR2B channel. The presence of the phosphorylation motif in Kir6.1, but not in its close relative Kir6.2, suggests that the vascular K(ATP) channel may have undergone evolutionary optimization, allowing it to be regulated by a variety of vasoconstricting hormones and neurotransmitters. |
| ISSN | 00219258 |
| e-ISSN | 1083351X |
| Journal | Journal of Biological Chemistry |
| Issue Number | 5 |
| Volume Number | 283 |
| Language | English |
| Publisher | American Society for Biochemistry and Molecular Biology (United States) |
| Publisher Date | 2008-02-01 |
| Publisher Place | United States |
| Access Restriction | Open |
| Subject Keyword | KATP Channels Antagonists & Inhibitors Potassium Channels, Inwardly Rectifying Chemistry Metabolism Protein Kinase C ATP-Binding Cassette Transporters Genetics Amino Acid Motifs Amino Acid Sequence Animals Cell Line In Vitro Techniques Kinetics Mice Molecular Sequence Data Mutagenesis, Site-Directed Phosphorylation Potassium Channels Protein Structure, Tertiary Receptors, Drug Recombinant Fusion Proteins Sequence Homology, Amino Acid Sulfonylurea Receptors Research Support, N.I.H., Extramural Biochemistry Molecular Biology |
| Content Type | Text |
| Resource Type | Article |
| Subject | Cell Biology Biochemistry Molecular Biology |
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