Kir6.1- and SUR2-dependent KATP overactivity disrupts intestinal motility in murine models of Cantú syndrome

Abstract

Cantú syndrome (CS), caused by gain-of-function (GOF) mutations in pore-forming (Kir6.1, KCNJ8 ) and accessory (SUR2, ABCC9 ) ATP-sensitive potassium (K ATP ) channel subunit genes, is frequently accompanied by gastrointestinal (GI) dysmotility, and we describe 1 CS patient who required an implanted intestinal irrigation system for successful stooling. We used gene-modified mice to assess the underlying K ATP channel subunits in gut smooth muscle and to model the consequences of altered K ATP channels in CS gut. We show that Kir6.1/SUR2 subunits underlie smooth muscle K ATP channels throughout the small intestine and colon. Knockin mice, carrying human KCNJ8 and ABCC9 CS mutations in the endogenous loci, exhibited reduced intrinsic contractility throughout the intestine, resulting in death when weaned onto solid food in the most severely affected animals. Death was avoided by weaning onto a liquid gel diet, implicating intestinal insufficiency and bowel impaction as the underlying cause, and GI transit was normalized by treatment with the K ATP inhibitor glibenclamide. We thus define the molecular basis of intestinal K ATP channel activity, the mechanism by which overactivity results in GI insufficiency, and a viable approach to therapy.

KATP Channel Function: More than Meets the Eye

“…Very recently, York et al reported that mice carrying Cantú K ATP mutations also exhibit reduced intestinal contractility, potentially accounting for the gastrointestinal dysmotility frequently seen in Cantú patients. 7 This study uncovers a previously unappreciated role of the Kir6.1/SUR2B channel in the gastrointestinal tract, raising the possibility that this channel holds additional functions yet to be discovered in smooth muscles in other tissues.…”

Strategies to gain novel Alzheimer’s disease diagnostics and therapeutics using modulators of ABCA transporters

“…Several drugs and drug-like compounds have already been demonstrated to be pan-ABC transporter modulators interacting also with ABCA transporters. These drugs and drug-like compounds are, for example, cyclosporine A (9 targets of 4 subfamilies: ABCA1, 245 ABCB1, 20 ABCB4, 552 ABCB11, 553 ABCC1–2, 24 , 554 ABCC10, 26 and ABCG1–2 555 , 556 ), glibenclamide (8 targets of 4 subfamilies: ABCA1, 270 ABCB11, 553 ABCC1, 24 ABCC5, 557 ABCC7–9, 558 - 560 and ABCG2 554 ), imatinib (6 targets of 4 subfamilies: ABCA3, 426 ABCB1, 561 ABCB11, 553 ABCC1, 561 ABCC10, 561 and ABCG2 561 ), probenecid (8 targets of 2 subfamilies: ABCA8, 222 ABCC1–6, 24 , 26 , 562 - 564 ABCC10 565 ), verapamil (9 targets of 4 subfamilies: ABCA8, 222 ABCB1, 20 ABCB4–5, 552 , 566 ABCB11, 567 ABCC1, 24 ABCC4, 568 ABCC10, 565 and ABCG2 554 ), and verlukast (11 targets of 4 subfamilies: ABCA8, 222 ABCB4, 552 ABCB11, 553 ABCC1–5, 24 , 554 , 557 , 564 , 569 ABCC10–11, 26 , 570 ABCG2 554 ). In silico analyses with verapamil and verlukast supported the notion of addressing the multitarget binding site in ABCA7.…”

Lymphatic contractile dysfunction in mouse models of Cantú Syndrome with KATP channel gain-of-function

“…Therefore, in the present study we investigated lymphatic function in recently developed “Cantú” mouse models, in which CS-associated mutations in Kir6.1 (V65M) or in SUR2 (A478V or R1154Q), were introduced into the respective endogenous murine loci using CRISPR/Cas9 engineering. The systemic consequences of these mutations for cardiovascular, 11 , 12 , 32–34 skeletal muscle, 35 , 36 and gastrointestinal 37 function have been recently investigated. Mirroring what is observed in CS patients, these mice exhibit dramatically enlarged hearts with increased ejection fraction and increased contractility.…”

“…This early death is particularly prominent shortly after weaning, and potentially reflects gastro-intestinal complications, since it is partially avoided by liquid diet. 12 , 37 The most common (>30%) CS-associated variants result in mutation R1154Q (or less commonly R1154W) at a single residue in SUR2. A third mouse, in which this variant was introduced to the ABCC9 locus by CRISPR mutation, also resulted in CS-like symptoms, but these were very mild, in this case due to an additional alternate splicing consequence that results in a decrease in the number of functional channels, 34 but which appears to not occur in human tissues.…”