ATP-Sensitive Potassium Channels in Cardiovascular and Metabolic Systems

ATP-sensitive potassium (KATP) channels are octameric complexes that couple cellular energy states to membrane excitability across diverse tissues. Each channel comprises four inward-rectifier K+ channel subunits (Kir6.x) and four regulatory sulfonylurea receptor (SUR) subunits. In pancreatic β-cells, Kir6.2/SUR1 channels sense the ATP/ADP ratio and regulate insulin secretion. In the heart and vasculature, Kir6.2/SUR2A channels protect cardiomyocytes during ischaemia by shortening action potentials, while Kir6.1/SUR2B assemblies in vascular smooth muscle and endothelium fine-tune vascular tone and endothelial Ca2+ signalling. Genetic mutations that alter channel gating or trafficking underlie neonatal diabetes, congenital hyperinsulinism and Cantu syndrome, illustrating the clinical significance of KATP control of metabolic homeostasis and cardiovascular protection. Advances in structural biology, electrophysiology and in vivo models continue to reveal mechanisms of nucleotide and lipid regulation, subunit diversity and pathological adaptations, paving the way for targeted interventions in metabolic and cardiovascular disease.

Research from Nature Portfolio

Recent structural studies have resolved an open conformation of a neonatal diabetes-associated Kir6.2-SUR1 KATP channel bound to phosphatidylinositol 4,5-bisphosphate (PIP2) at two distinct sites. High-resolution cryo-EM maps demonstrate a conserved canonical PIP2 binding pocket and a non-canonical site at the Kir6.2–SUR1 interface. Functional assays reveal that both lipid interactions synergise to stabilise the open state by widening the inhibitory ATP pocket and diminishing ATP affinity. A specific neonatal diabetes mutation (Kir6.2-Q52R) enhances cation–π bonding with SUR1, further favouring channel opening. These insights uncover the structural basis for antagonistic regulation by ATP and PIP2, clarify the gating mechanism of pancreatic KATP channels and suggest routes for modulating channel activity in metabolic disorders.

ATP-Sensitive Potassium Channels in Cardiovascular and Metabolic Systems publication trend

The graph below shows the total number of articles in atp-sensitive potassium channels in cardiovascular and metabolic systems across all publications each year (not limited to Nature Index journals).

Technical terms

ATP-sensitive potassium (KATP) channel: Metabolic sensor that links intracellular ATP/ADP levels to membrane excitability.

Kir6.x subunits: Pore-forming inward-rectifier potassium channel proteins that determine ion conductance and gating.

Sulfonylurea receptor (SUR) subunits: Regulatory ABC transporter modules that modulate KATP channel response to nucleotides and drugs.

Phosphatidylinositol 4,5-bisphosphate (PIP2): Anionic phospholipid that binds to KATP channels to stabilise the open conformation.

Cryo-electron microscopy (cryo-EM): Imaging technique that determines macromolecular structures at near-atomic resolution under cryogenic conditions.

Constitutively active: Channel behaviour in which the pore remains open under resting physiological conditions, independent of typical gating stimuli.

References

1. Structure of an open KATP channel reveals tandem PIP2 binding sites mediating the Kir6.2 and SUR1 regulatory interface. Nature Communications (2024).
2. Identification and characterisation of functional Kir6.1‐containing ATP‐sensitive potassium channels in the cardiac ventricular sarcolemmal membrane. British Journal of Pharmacology (2024).
3. Mitochondrial Ca2+-coupled generation of reactive oxygen species, peroxynitrite formation, and endothelial dysfunction in Cantú syndrome. JCI Insight (2024).
4. Novel loss-of-function variants expand ABCC9-related intellectual disability and myopathy syndrome. Brain (2024).