Signaling in channel/enzyme multimers: ATPase transitions in SUR module gate ATP-sensitive K+ conductance

ATP-sensitive potassium (K-ATP) channels are bifunctional multimers assembl ed by an ion conductor and a sulfonylurea receptor (SUR) ATPase. Sensitive to ATP/ADP, K-ATP channels are vital metabolic sensors. However, channel re gulation by competitive ATP/ADP binding would require oscillations in intra cellular nucleotides incompatible with cell survival. We found that channel behavior is determined by the ATPase-driven engagement of SUR into discret e conformations. Capture of the SUR catalytic cycle in prehydrolytic states facilitated pore closure, while recruitment of posthydrolytic intermediate s translated in pore opening. In the cell, channel openers stabilized posth ydrolytic states promoting K-ATP channel activation. Nucleotide exchange be tween intrinsic ATPase and ATP/ADP-scavenging systems defined the lifetimes of specific SUR conformations gating K-ATP channels. Signal transduction t hrough the catalytic module provides a paradigm for channel/enzyme operatio n and integrates membrane excitability with metabolic cascades.