The CFTR protein, which is involved in Cystic Fibrosis (CF), is regulated by divalent cations. An increased intracellular Mg2+ ([Mg2+]i) concentration induces a decreased expression of the CFTR’s mARN. At the opposite, a decreased [Mg2+]i reduces the rate of opening and closing of CFTR and, therefore alters its chloride channel activity. Thus, [Mg2+] is an important ion for CFTR as shown by the major role of Mg-ATP when compared to that of ATP alone.
The transient receptor potential melastatin 7 channel (TRPM7), discovered in 2001, is an ubiquitous channel with a main function as a [Mg2+]i regulator. It is itself regulated by [Mg2+]i. A 300 M [Mg2+]i concentration is suffisant to induce its inhibition. TRPM7 is also sensitive to intracellular pH and [Cl-]i.
Because [Mg2+]i concentration has to be well regulated for a normal CFTR’s expression and function, and because TRPM7 regulates [Mg2+]i concentration, our aim is to study the involvement of TRPM7 in CF.
Our objective is to search for a possible expression and/or activity dysregulation of TRPM7 in CF cells, to make a link with the altered expression and/or activity of CFTR. For this purpose we shall measure [Mg2+]i in wild-type-CFTR, G551D-CFTR and F508del-CFTR expressing cells. The basal TRPM7’s expression (mRNA and protein) and activity (patch-clamp) will be assessed in these cells and correlated to the alteration of CFTR. The effect of a blockage of TRPM7 by a drug will be assessed upon CFTR‘s function. Finally, the cellular co-distribution of both TRPM7 and CFTR will be assessed by confocal imaging.
To our knowledge this is the first project aimed to assess the role of TRPM7 in the CF’s pathophysiology. Because TRPM7 is involved in many diseases such as bone disease, cardiovascular disease and diabetes and because it is involved in normal cellular homeostasis, it could be of a therapeutic interest in CF.