The gastrointestinal K_ATP-ERK signaling axis: Molecular mechanisms, pharmacological opportunities, and emerging...

ATP-sensitive potassium channels are metabolic sensors that couple intracellular nucleotide availability to membrane excitability, calcium signaling, mitochondrial function, and cell survival. Growing evidence identifies K_ATP channels as essential regulators of gastrointestinal physiology. They are expressed in smooth muscle, enteric neurons, interstitial cells of Cajal, epithelial and enteroendocrine cells, microvascular cells, pericytes, and liver, where they contribute to motility, secretion, barrier integrity, nutrient sensing, vascular regulation, and mucosal protection. In parallel, ERK1/2 are central effectors of the MAPK pathway, controlling epithelial renewal, inflammation, fibrosis, apoptosis, and tissue repair. This review proposes an integrated K_ATP-ERK signaling network that regulates gastrointestinal homeostasis.

PubMed and Scopus were searched for relevant studies using combinations of the terms "ERK" AND "K_ATP channels" AND "cardiovascular" OR "gastrointestinal".

Evidence supports functional crosstalk between K_ATP channels and ERK signaling. In this framework, K_ATP channels act as metabolic rheostats, whereas ERK integrates redox, growth factor, and stress-related signals. Acute K_ATP activation promotes adaptation by preserving mitochondrial function and epithelial barrier integrity, whereas chronic channel overactivation, as observed in Cantú syndrome caused by gain-of-function mutations in ABCC9 or KCNJ8, may induce maladaptive remodeling, tight junction disruption, apoptosis, fibrosis, and dysmotility. The potential involvement of FGFR/Klotho signaling as an upstream ERK regulator, together with K_ATP/ERK pharmacological modulation, FGF/Klotho-based therapies, and biosensor technologies for pathway monitoring in organoids and gut-on-chip models, is also discussed.

The K_ATP-ERK-FGFR/Klotho framework links ion-channel pharmacology with gastrointestinal biology, providing a foundation for biomarker discovery, therapeutic development, and precision medicine approaches in gastrointestinal disorders.