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

Nathaniel W York,Zili Xie,Helen Parker,Colin G Nichols,Dorothy K Grange,Maria Sara Remedi,Sarah K England,Zihan Yan,Maham Akbar Waheed,Hongzhen Hu,David Tyus

doi:10.1172/jci.insight.141443

Abstract

Cantú syndrome (CS), caused by gain-of-function (GOF) mutations in pore-forming (Kir6.1, KCNJ8) and accessory (SUR2, ABCC9) ATP-sensitive potassium (KATP) 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 KATP channel subunits in gut smooth muscle and to model the consequences of altered KATP channels in CS gut. We show that Kir6.1/SUR2 subunits underlie smooth muscle KATP 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 KATP inhibitor glibenclamide. We thus define the molecular basis of intestinal KATP channel activity, the mechanism by which overactivity results in GI insufficiency, and a viable approach to therapy.

Highlights

ATP-sensitive potassium (KATP) channels, characterized by inhibition by intracellular ATP and activation by Mg-ADP, effectively link membrane excitability to metabolic state
Through analysis of mice in which Cantú syndrome (CS) mutations were introduced to the equivalent loci in the mouse KCNJ8 and ABCC9 genes, we previously demonstrated that vascular smooth muscle hypoexcitability underlies the cardiovascular features of CS [3, 22], but the multifaceted presentation in other tissues is not explained by chronic vascular dilation
GI motility arises from the coordinated activity of the intestinal smooth muscle cells (SMC), interstitial cells of Cajal (ICC), and PDGFRα+ cell (SIP) syncytium, the activity of which is in turn modulated by the enteric nervous system (ENS), allowing for the coordination of motility patterns

Summary

Introduction

ATP-sensitive potassium (KATP) channels, characterized by inhibition by intracellular ATP and activation by Mg-ADP, effectively link membrane excitability to metabolic state. Functional channels are composed of hetero-octameric complexes: 4 Kir6.x pore forming subunits, responsible for ATP inhibition, and 4 regulatory SURx subunits responsible for Mg-ADP activation. Kir6.2 and SUR1 are predominantly expressed in the pancreas and neurons, Kir6.2 and SUR2A in cardiomyocytes, and Kir6.1 and SUR2B in vascular smooth muscle [6,7,8,9]. We demonstrate first that intestinal contractility is reliant on Kir6.1 and SUR2 expression in smooth muscle and, secondly, that pathogenic mutations within ABCC9 and KCNJ8, both of which underlie Cantú syndrome (CS), result in impaired contractility and motility in both small intestine and colon

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