Sie befinden Sich nicht im Netzwerk der Universität Paderborn. Der Zugriff auf elektronische Ressourcen ist gegebenenfalls nur via VPN oder Shibboleth (DFN-AAI) möglich. mehr Informationen...
Function and regulation of TRPM7, as well as intracellular magnesium content, are altered in cells expressing ΔF508-CFTR and G551D-CFTR
Ist Teil von
Cellular and molecular life sciences : CMLS, 2016-09, Vol.73 (17), p.3351-3373
Ort / Verlag
Cham: Springer International Publishing
Erscheinungsjahr
2016
Link zum Volltext
Quelle
SpringerLink Journals
Beschreibungen/Notizen
Cystic fibrosis (CF), one of the most common fatal hereditary disorders, is caused by mutations in the cystic fibrosis transmembrane conductance regulator (
CFTR
) gene. The CFTR gene product is a multidomain adenosine triphosphate-binding cassette (ABC) protein that functions as a chloride (Cl
−
) channel that is regulated by intracellular magnesium [Mg
2+
]
i
. The most common mutations in
CFTR
are a deletion of a phenylalanine residue at position 508 (ΔF508-CFTR, 70–80 % of CF phenotypes) and a Gly551Asp substitution (G551D-CFTR, 4–5 % of alleles), which lead to decreased or almost abolished Cl
−
channel function, respectively. Magnesium ions have to be finely regulated within cells for optimal expression and function of CFTR. Therefore, the melastatin-like transient receptor potential cation channel, subfamily M, member 7 (TRPM7), which is responsible for Mg
2+
entry, was studies and [Mg
2+
]
i
measured in cells stably expressing wildtype CFTR, and two mutant proteins (ΔF508-CFTR and G551D-CFTR). This study shows for the first time that [Mg
2+
]
i
is decreased in cells expressing ΔF508-CFTR and G551D-CFTR mutated proteins. It was also observed that the expression of the TRPM7 protein is increased; however, membrane localization was altered for both ΔF508del-CFTR and G551D-CFTR. Furthermore, both the function and regulation of the TRPM7 channel regarding Mg
2+
is decreased in the cells expressing the mutated CFTR. Ca
2+
influx via TRPM7 were also modified in cells expressing a mutated CFTR. Therefore, there appears to be a direct involvement of TRPM7 in CF physiopathology. Finally, we propose that the TRPM7 activator Naltriben is a new potentiator for G551D-CFTR as the function of this mutant increases upon activation of TRPM7 by Naltriben.