Kir6.1- and SUR2-Dependent KATP Overactivity Caused Intestinal Tight Junction Protein Alterations in the Intestinal Epithelium in Murine Models of Cantú Syndrome

Abstract ID 129414 Poster Board 207 Cantu syndrome (CS) is a rare genetic disorder caused by gain-of-function (GOF) mutations in pore-forming (Kir6.1, KCNJ8) and accessory (SUR2, ABCC9) ATP-sensitive potassium (KATP) channel subunit genes, characterized by distinctive facial features, cardiac abnormalities, hypertrichosis, and skeletal abnormalities. One of the lesser-known but significant aspects of CS is its association with gastrointestinal (GI) dysmotility which is observed in CS mice [1]. A dysfunction of KATP channels has been found in various diseases affecting GI disorders, including some forms of irritable bowel syndrome (IBS) and motility disorders like gastroparesis [2]. In the CS conditions, the overactivity of KATP channels might disrupt the normal patterns of smooth muscle contractions, leading to alterations in intestinal motility. Furthermore, KATP channels are present in neurons and regulate neurotransmitter release and neuronal excitability. Overactivity of KATP channels in enteric neurons or nerves innervating the intestines could dysregulate neural motility control. While the precise mechanisms underlying the potential interaction between KATP channels and tight junctions (TJ) protein structures intercellular that play a role critical for building the epithelial barrier and maintaining epithelial polarity remain to be fully elucidated, emerging evidence suggests that alterations in cellular signaling, energy metabolism, and ion homeostasis associated with KATP channel dysfunction could contribute to disruptions in TJ structure and function. The characterization of CS mice with A478V substitution in SUR2 and V65M in Kir6.1 showed reduced forelimb strength and amplitude of diaphragm movement; RT-PCR evaluation on intestinal smooth muscle detected the expression of both Kir6 subunits and SUR2A/B specifically in the muscle layer of all gastrointestinal tract segments. Investigation of intestinal biopsies showed significant alterations of intestinal TJ proteins, including Zonula occludens (ZO-1), occluding, and claudins 1 and 2 in CS mice vs. control mice, with the Kir6.1 and SUR2 colocalizing with claudin 1. In summary, KATP overactivity can disrupt the normal regulation of intestinal motility by affecting smooth muscle function, and neural regulation, and contributing to GI disorders. Understanding the role of KATP channels in intestinal motility may lead to developing new therapeutic approaches for managing motility disorders and related GI conditions. KATP channels are indeed relevant drug targets [3]. York NW, Parker H, Xie Z, Tyus D, Waheed MA, Yan Z, Grange DK, Remedi MS, England SK, Hu H, Nichols CG. Kir6.1- and SUR2-dependent KATP overactivity disrupts intestinal motility in murine models of Cantú syndrome. JCI Insight. 2020 Nov 10;5(23):e141443. doi: 10.1172/jci.insight.141443. PMID: 33170808; PMCID: PMC7714409. Maqoud F, Tricarico D, Mallamaci R, Orlando A, Russo F. The Role of Ion Channels in Functional Gastrointestinal Disorders (FGID): Evidence of Channelopathies and Potential Avenues for Future Research and Therapeutic Targets. Int J Mol Sci. 2023 Jul 4;24(13):11074. doi: 10.3390/ijms241311074. PMID: 37446251; PMCID: PMC10342167. Maqoud F, Scala R, Tragni V, Pierri CL, Perrone MG, Scilimati A, Tricarico D. Zoledronic Acid as a Novel Dual Blocker of KIR6.1/2-SUR2 Subunits of ATP-Sensitive K⁺ Channels: Role in the Adverse Drug Reactions. Pharmaceutics. 2021 Aug 27;13(9):1350. doi: 10.3390/pharmaceutics13091350