Long Chain Coenzyme A Esters Activate the Pore-forming Subunit (Kir6.2) of the ATP-regulated Potassium Channel

The ATP-dependent potassium (KATP) channel in the pancreatic β-cell is a complex of two proteins, the pore-forming Kir6.2 and the sulfonylurea receptor type 1 (SUR1). Both subunits are required for functional KATP channels because expression of Kir6.2 alone does not result in measurable currents. Ho...

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Bibliographic Details
Published in:The Journal of biological chemistry 1998-11, Vol.273 (47), p.31395-31400
Main Authors: Bränström, Robert, Leibiger, Ingo B., Leibiger, Barbara, Corkey, Barbara E., Berggren, Per-Olof, Larsson, Olof
Format: Article
Language:English
Subjects:
Acyl Coenzyme A - chemistry
Acyl Coenzyme A - pharmacology
Adenosine Diphosphate - pharmacology
Adenosine Triphosphate - pharmacology
Animals
ATP-Binding Cassette Transporters
Electric Conductivity
Electrophysiology - methods
Ion Channel Gating
KATP Channels
Kinetics
Medicin och hälsovetenskap
Mice
Oocytes
Peptide Fragments - drug effects
Potassium Channels - deficiency
Potassium Channels - drug effects
Potassium Channels - genetics
Potassium Channels - metabolism
Potassium Channels, Inwardly Rectifying
Receptors, Drug - deficiency
Recombinant Proteins - metabolism
Structure-Activity Relationship
Sulfonylurea Receptors
Xenopus laevis
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Summary:The ATP-dependent potassium (KATP) channel in the pancreatic β-cell is a complex of two proteins, the pore-forming Kir6.2 and the sulfonylurea receptor type 1 (SUR1). Both subunits are required for functional KATP channels because expression of Kir6.2 alone does not result in measurable currents. However, truncation of the last 26 or 36 amino acids of the C terminus of Kir6.2 enables functional expression of the pore-forming protein in the absence of SUR1. Thus, by using the truncated form of Kir6.2, expressed in the absence and presence of SUR1, it has been shown that the site at which ATP mediates channel inhibition is likely to be situated on Kir6.2. We have now examined the effects of long chain acyl-CoA (LC-CoA) esters on the C-terminally truncated mouse Kir6.2Δ365–390 (Kir6.2ΔC26) in inside-out patches isolated from Xenopus laevis oocytes. LC-CoA esters, saturated (C14:0, C16:0) and unsaturated (C18:1), increased Kir6.2ΔC26 currents, whereas short and medium chain CoA esters (C3:0, C8:0, C12:0) were unable to affect channel activity. The LC-CoA esters were also able to counteract the blocking effect of ATP on Kir6.2ΔC26. The stimulatory effect of the esters could be explained by the induction of a prolonged open state of Kir6.2ΔC26. In the presence of the esters, channel open time was increased approximately 3-fold, which is identical to what was obtained in the native mouse KATP channel. Coexpression of SUR1 together with Kir6.2ΔC26 did not further increase the ability of LC-CoA esters to stimulate channel activity. We conclude that Kir6.2 is the primary target for LC-CoA esters to activate the KATP channel and that the esters are likely to induce a conformational change by a direct interference with the pore-forming subunit, leading to openings of long duration.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.273.47.31395