CFTR and Ca Signaling in Cystic Fibrosis

Abstract

Among the diverse physiological functions exerted by calcium signaling in living cells, its role in the regulation of protein biogenesis and trafficking remains incompletely understood. In cystic fibrosis (CF) disease the most common CF transmembrane conductance regulator (CFTR) mutation, F508del-CFTR generates a misprocessed protein that is abnormally retained in the endoplasmic reticulum (ER) compartment, rapidly degraded by the ubiquitin/proteasome pathway and hence absent at the plasma membrane of CF epithelial cells. Recent studies have demonstrated that intracellular calcium signals consequent to activation of apical G-protein-coupled receptors by different agonists are increased in CF airway epithelia. Moreover, the regulation of various intracellular calcium storage compartments, such as ER is also abnormal in CF cells. Although the molecular mechanism at the origin of this increase remains puzzling in epithelial cells, the F508del-CFTR mutation is proposed to be the onset of abnormal Ca(2+) influx linking the calcium signaling to CFTR pathobiology. This article reviews the relationships between CFTR and calcium signaling in the context of the genetic disease CF.

Keywords: CFTR; calcium signaling; calcium stores; cystic fibrosis; pharmacology; trafficking.

Figure 1

Correlation between ER morphology, IP3R clustering, and IP3R Ca²⁺ release plasma. (A) In Non-CF cells, the ER was expended at the totality of cell surface, IP3Rs are distant between others and the IP3R ER Ca²⁺ release was normal (B) In CF cells, the F508del-CFTR was trapped into ER. The ER was concentrated around the nucleus. IP3Rs are more clustered and the Ca²⁺ propagation wave was abnormally increased. ER staining was performed with ER-tracker (1 μM during 15 min). The IP3R Ca²⁺ release was measured by using NP-EGTA or IP3-caged techniques.

Figure 2

Proposed model linking the F508del-CFTR mutation and Ca²⁺ homeostasis in airway epithelial cell line. (Left panel) In CF airway epithelial phenotype, in absence of bacterial infection, the F508del-CFTR mutation caused the trapped of mutated CFTR protein into the ER, followed by the ER network condensation, inducing the IP3R clustering. The final consequence was the increased of IP3R activity. Moreover, the CFTR absence of the plasma membrane (PM) induced a hyper-activity of TRPC6 Ca²⁺ channel. (Right panel) The abnormal F508del-CFTR trafficking correction (pharmacologically or low temperature incubation) induced an ER network expansion. IP3Rs are more distant from each others, leading to reduce Ca²⁺ release. At PM level, the F508del-CFTR interacted with TRPC6. This interaction seems to induce a normalization of TRPC6 activity.