Signaling in channel/enzyme multimers: ATPase transitions in SUR module gate ATP-sensitive K+ conductance.
ATP-sensitive potassium (K(ATP)) channels are bifunctional multimers assembled by an ion conductor and a sulfonylurea receptor (SUR) ATPase. Sensitive to ATP/ADP, K(ATP) channels are vital metabolic sensors. However, channel regulation by competitive ATP/ADP binding would require oscillations in intracellular nucleotides incompatible with cell survival. We found that channel behavior is determined by the ATPase-driven engagement of SUR into discrete conformations. Capture of the SUR catalytic cycle in prehydrolytic states facilitated pore closure, while recruitment of posthydrolytic intermediates translated in pore opening. In the cell, channel openers stabilized posthydrolytic states promoting K(ATP) channel activation. Nucleotide exchange between intrinsic ATPase and ATP/ADP-scavenging systems defined the lifetimes of specific SUR conformations gating K(ATP) channels. Signal transduction through the catalytic module provides a paradigm for channel/enzyme operation and integrates membrane excitability with metabolic cascades.
Zingman
L V
LV
Division of Cardiovascular Diseases, Department of Medicine, Mayo Clinic, Mayo Foundation Rochester, MN 55905, USA.
Alekseev
A E
AE
Bienengraeber
M
M
Hodgson
D
D
Karger
A B
AB
Dzeja
P P
PP
Terzic
A
A
D018528:ATP-Binding Cassette Transporters; D000244:Adenosine Diphosphate / Q000378:metabolism / Q000494:pharmacology; D000251:Adenosine Triphosphatases / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*; D000255:Adenosine Triphosphate / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D001608:Beryllium / Q000494:pharmacology; D001665:Binding Sites; D004553:Electric Conductivity; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005459:Fluorides / Q000494:pharmacology; D006168:Guinea Pigs; D006868:Hydrolysis; D015640:Ion Channel Gating; D015221:Potassium Channels / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D024661:Potassium Channels, Inwardly Rectifying; D011487:Protein Conformation; D011955:Receptors, Drug / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D011994:Recombinant Proteins; D015398:Signal Transduction; D064233:Sulfonylurea Receptors; D014638:Vanadates / Q000494:pharmacology
D018528:ATP-Binding Cassette Transporters; D004791:Enzyme Inhibitors; D015221:Potassium Channels; D024661:Potassium Channels, Inwardly Rectifying; D011955:Receptors, Drug; D011994:Recombinant Proteins; D064233:Sulfonylurea Receptors; D014638:Vanadates; C035982:beryllium fluoride; D000244:Adenosine Diphosphate; D000255:Adenosine Triphosphate; D000251:Adenosine Triphosphatases; D001608:Beryllium; D005459:Fluorides