Guanylate cyclase 2C agonism corrects CFTR mutants

Arora, Kavisha; Huang, Yunjie; Mun, Kyu-Shik; Yarlagadda, Sunitha; Sundaram, Nambirajan; Kessler, Marco M.; Hannig, Gerhard; Kurtz, Caroline B.; Silos‐Santiago, Inmaculada; Helmrath, Michael A.; Palermo, Joseph J.; Clancy, John; Steinbrecher, Kris A.; Naren, Anjaparavanda P.

doi:10.1172/jci.insight.93686

Cited by 19 publications

(19 citation statements)

References 41 publications

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“…In addition, studies of CFTR modulation in rectal organoids have more rapid assay throughput as compared to short circuit current measurements in HBE planar cultures. Enteroids derived from duodenal biopsies can provide a rapid readout within a few days of acquisition, but currently the lack of progenitor cell isolation has limited their use [40]. T his may be able to be overcome with further experience.…”

Section: Preclinical Model Systems To Test Cftr Therapiesmentioning

confidence: 99%

CFTR modulator theratyping: Current status, gaps and future directions

Clancy

Cotton

Donaldson

et al. 2019

Journal of Cystic Fibrosis

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Section: Preclinical Model Systems To Test Cftr Therapiesmentioning

confidence: 99%

CFTR modulator theratyping: Current status, gaps and future directions

Clancy

Cotton

Donaldson

et al. 2019

Journal of Cystic Fibrosis

Self Cite

234

198

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“…using CFTRinh-172) or loss-of-function Diarrheagenic complex in cholera mutation in CFTR (e.g. F508del CFTR) makes CTX less effective or ineffective in inducing secretion in ligated ileal loops in mice (16,17). Whereas CTX induced significant fluid accumulation in Adcy6 f/f mice, this phenomenon was largely absent in Adcy6 ⌬/⌬ mice at a CTX dose of 1 g and dramatically impaired at a dose of 10 g (Fig.…”

Section: Adcy6 ⌬/⌬ Mice Are Protected Against Ctx-induced Diarrheamentioning

confidence: 98%

“…Having determined that AC6 and CFTR interact at the plasma membrane and that loss of AC6 fails to elicit cAMP response in the presence of CTX, we next investigated intestinal fluid secretion in Adcy6 ⌬/⌬ mice upon CTX challenge. We used the closed ileal loop model in mice to test CTX-induced fluid secretion (3,6,16,17). CTX injected into the ligated loops induces hyperactivation of CFTR Cl Ϫ channel via cAMP production, causing a voluminous fluid secretion and accumulation in the closed loops.…”

Section: Adcy6 ⌬/⌬ Mice Are Protected Against Ctx-induced Diarrheamentioning

confidence: 99%

AC6 is the major adenylate cyclase forming a diarrheagenic protein complex with cystic fibrosis transmembrane conductance regulator in cholera

Thomas

Ramananda

Mun

et al. 2018

Journal of Biological Chemistry

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The World Health Organization(WHO) has reported a worldwide surge in cases of cholera caused by the intestinal pathogen , and, combined, such surges have claimed several million lives, mostly in early childhood. Elevated cAMP production in intestinal epithelial cells challenged with cholera toxin (CTX) results in diarrhea due to chloride transport by a cAMP-activated channel, the cystic fibrosis transmembrane conductance regulator (CFTR). However, the identity of the main cAMP-producing proteins that regulate CFTR in the intestine and may be relevant for secretory diarrhea is unclear. Here, using RNA-Seq to identify the predominant AC isoform in mouse and human cells and extensive biochemical analyses for further characterization, we found that the cAMP-generating enzyme adenylate cyclase 6 (AC6) physically and functionally associates with CFTR at the apical surface of intestinal epithelial cells. We generated epithelium-specific AC6 knockout mice and demonstrated that CFTR-dependent fluid secretion is nearly abolished in AC6 knockout mice upon CTX challenge in ligated ileal loops. Furthermore, loss of AC6 function dramatically impaired CTX-induced CFTR activation in human and mouse intestinal spheroids. Our finding that the CFTR-AC6 protein complex is the key mediator of CTX-associated diarrhea may facilitate development of antidiarrheal agents to manage cholera symptoms and improve outcomes.

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“…Importantly, cGMPs activate CFTR in a PKA-independent manner (Kelley et al, 1997b), and promote trafficking of CFTR to the plasma membrane of the intestinal epithelium (Ahsan et al, 2017). Stimulating this pathway may also correct/potentiate mutant CFTR and thus ameliorate the intestinal fluid deficit in the CF intestine (Arora et al, 2017). Thus, by increasing cGMP cellular levels (Foresti and Motterlini, 1999), CO may help stimulate wild-type and mutant CFTR ion transport.…”

Section: Relevance To Cfmentioning

confidence: 99%

Targeting the Heme Oxygenase 1/Carbon Monoxide Pathway to Resolve Lung Hyper-Inflammation and Restore a Regulated Immune Response in Cystic Fibrosis

et al. 2020

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In individuals with cystic fibrosis (CF), lung hyper-inflammation starts early in life and is perpetuated by mucus obstruction and persistent bacterial infections. The continuous tissue damage and scarring caused by non-resolving inflammation leads to bronchiectasis and, ultimately, respiratory failure. Macrophages (MFs) are key regulators of immune response and host defense. We and others have shown that, in CF, MFs are hyper-inflammatory and exhibit reduced bactericidal activity. Thus, MFs contribute to the inability of CF lung tissues to control the inflammatory response or restore tissue homeostasis. The non-resolving hyper-inflammation in CF lungs is attributed to an impairment of several signaling pathways associated with resolution of the inflammatory response, including the heme oxygenase-1/carbon monoxide (HO-1/CO) pathway. HO-1 is an enzyme that degrades heme groups, leading to the production of potent antioxidant, anti-inflammatory, and bactericidal mediators, such as biliverdin, bilirubin, and CO. This pathway is fundamental to re-establishing cellular homeostasis in response to various insults, such as oxidative stress and infection. Monocytes/MFs rely on abundant induction of the HO-1/CO pathway for a controlled immune response and for potent bactericidal activity. Here, we discuss studies showing that blunted HO-1 activation in CFaffected cells contributes to hyper-inflammation and defective host defense against bacteria. We dissect potential cellular mechanisms that may lead to decreased HO-1 induction in CF cells. We review literature suggesting that induction of HO-1 may be beneficial for the treatment of CF lung disease. Finally, we discuss recent studies highlighting how endogenous HO-1 can be induced by administration of controlled doses of CO to reduce lung hyper-inflammation, oxidative stress, bacterial infection, and dysfunctional ion transport, which are all hallmarks of CF lung disease.

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Guanylate cyclase 2C agonism corrects CFTR mutants

Cited by 19 publications

References 41 publications

CFTR modulator theratyping: Current status, gaps and future directions

CFTR modulator theratyping: Current status, gaps and future directions

AC6 is the major adenylate cyclase forming a diarrheagenic protein complex with cystic fibrosis transmembrane conductance regulator in cholera

Targeting the Heme Oxygenase 1/Carbon Monoxide Pathway to Resolve Lung Hyper-Inflammation and Restore a Regulated Immune Response in Cystic Fibrosis

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