Advertisement

 

 

Guanylate cyclase 2C agonism corrects CFTR mutants.

Guanylate cyclase 2C agonism corrects CFTR mutants.
Author Information (click to view)

Arora K, Huang Y, Mun K, Yarlagadda S, Sundaram N, Kessler MM, Hannig G, Kurtz CB, Silos-Santiago I, Helmrath M, Palermo JJ, Clancy JP, Steinbrecher KA, Naren AP,


Arora K, Huang Y, Mun K, Yarlagadda S, Sundaram N, Kessler MM, Hannig G, Kurtz CB, Silos-Santiago I, Helmrath M, Palermo JJ, Clancy JP, Steinbrecher KA, Naren AP, (click to view)

Arora K, Huang Y, Mun K, Yarlagadda S, Sundaram N, Kessler MM, Hannig G, Kurtz CB, Silos-Santiago I, Helmrath M, Palermo JJ, Clancy JP, Steinbrecher KA, Naren AP,

Advertisement
Share on FacebookTweet about this on TwitterShare on LinkedIn

JCI insight 2017 10 052(19) doi 10.1172/jci.insight.93686
Abstract

Cystic fibrosis (CF) is a genetic disorder in which epithelium-generated fluid flow from the lung, intestine, and pancreas is impaired due to mutations disrupting CF transmembrane conductance regulator (CFTR) channel function. CF manifestations of the pancreas and lung are present in the vast majority of CF patients, and 15% of CF infants are born with obstructed gut or meconium ileus. However, constipation is a significantly underreported outcome of CF disease, affecting 47% of the CF patients, and management becomes critical in the wake of increasing life span of CF patients. In this study, we unraveled a potentially novel molecular role of a membrane-bound cyclic guanosine monophosphate-synthesizing (cGMP-synthesizing) intestinal enzyme, guanylate cyclase 2C (GCC) that could be targeted to ameliorate CF-associated intestinal fluid deficit. We demonstrated that GCC agonism results in functional rescue of murine F508del/F508del and R117H/R117H Cftr and CFTR mutants in CF patient-derived intestinal spheres. GCC coexpression and activation facilitated processing and ER exit of F508del CFTR and presented a potentially novel rescue modality in the intestine, similar to the CF corrector VX-809. Our findings identify GCC as a biological CFTR corrector and potentiator in the intestine.

Submit a Comment

Your email address will not be published. Required fields are marked *

1 × 3 =

[ HIDE/SHOW ]