The Mechanistic Links between Insulin and Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) Cl- Channel.

Yoshinori Marunaka

doi:10.3390/ijms18081767

Abstract

The cystic fibrosis transmembrane conductance regulator (CFTR) Cl− channel belongs to the ATP-binding cassette (ABC) transporter superfamily and regulates Cl− secretion in epithelial cells for water secretion. Loss-of-function mutations to the CFTR gene cause dehydrated mucus on the apical side of epithelial cells and increase the susceptibility of bacterial infection, especially in the airway and pulmonary tissues. Therefore, research on the molecular properties of CFTR, such as its gating mechanism and subcellular trafficking, have been intensively pursued. Dysregulated CFTR trafficking is one of the major pathological hallmarks in cystic fibrosis (CF) patients bearing missense mutations in the CFTR gene. Hormones that activate cAMP signaling, such as catecholamine, have been found to regulate the intracellular trafficking of CFTR. Insulin is one of the hormones that regulate cAMP production and promote trafficking of transmembrane proteins to the plasma membrane. The functional interactions between insulin and CFTR have not yet been clearly defined. In this review article, I review the roles of CFTR in epithelial cells, its regulatory role in insulin secretion, and a mechanism of CFTR regulation by insulin.

Highlights

Cystic fibrosis (CF) is the most frequent autosomal recessive lethal disorders in the Caucasian population, and results from loss-of-function mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene [1,2,3]
The CFTR Cl− channel is composed of five domains: (1) two membrane-spanning domains (MSD1 and MSD2) form the pore of the channel with a permeability to Cl− and HCO3−, secreting these ions across the membrane, and each domain is composed of six transmembrane segments (TM1–TM6 and TM7–TM12); (2) two cytosolic nucleotide-binding domains (NBD1 and NBD2), at which ATP is hydrolyzed, regulate channel gating; and (3) a regulatory domain (RD) containing multiple phosphorylation sites controls channel activity [3]
Akt1 and Akt2, which are the most important signaling cascades of insulin, show smaller responses to insulin in ∆F508-CFTR airway cells than that in wild-type CFTR airway cells [75]. These results indicate that the function of CFTR Cl− channels is required for insulin to stimulate glucose uptake, elevate the transepithelial resistance, and diminish the paracellular flux of small molecules in airway epithelial cells

Summary

Introduction

Cystic fibrosis (CF) is the most frequent autosomal recessive lethal disorders in the Caucasian population, and results from loss-of-function mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene [1,2,3]. These observations imply that CFTR Cl− channels play an important role in glucose-induced membrane depolarization, which stimulates insulin secretion in pancreatic β cells via the elevation of

Results

Conclusion