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MgATP activates the beta cell KATP channel by interaction with its SUR1 subunit
F M Gribble1, S J Tucker, T Haug
1University Laboratory of Physiology, Parks Road, Oxford OX1 3PT, United Kingdom.
Summary
Magnesium ATP (MgATP) activates ATP-sensitive potassium (KATP) channels by interacting with SUR1 subunits, challenging the long-held view that only MgADP activates these channels involved in insulin release.
Area of Science:
- Cellular physiology
- Molecular biology
- Endocrinology
Background:
- ATP-sensitive potassium (KATP) channels regulate insulin secretion in pancreatic beta cells.
- Glucose metabolism closes KATP channels, leading to insulin release.
- Current understanding posits MgADP activates and ATP inhibits KATP channels via Kir6.2 and SUR1 subunits.
Purpose of the Study:
- To investigate the role of MgATP in regulating KATP channel activity.
- To elucidate the specific subunits and domains involved in MgATP-mediated regulation.
- To challenge the established model of KATP channel metabolic control.
Main Methods:
- Electrophysiological recordings of wild-type and mutant KATP channels (Kir6.2/SUR1).
- Site-directed mutagenesis of SUR1 nucleotide-binding domains (NBDs) and Kir6.2.
- Assessment of channel activity in response to MgATP and Mg2+.
Main Results:
- MgATP stimulates KATP channel activity, an effect masked by ATP's inhibition.
- Mg2+ reduces ATP's inhibitory effect on wild-type channels.
- MgATP activates Kir6.2(R50G) mutant channels, with effects abolished by SUR1 NBD mutations.
- Kir6.2 alone shows no Mg2+ sensitivity.
Conclusions:
- MgATP, similar to MgADP, activates KATP channels through interaction with SUR1 NBDs.
- The regulatory role of MgATP in KATP channels is more complex than previously assumed.
- These findings refine the understanding of metabolic control of insulin secretion.