PIKfyve upregulates CFTR activity

E-M Gehring, RS Lam, G Siraskar, E Koutsouki, G Seebohm, ON Ureche, L Ureche, R Baltaev, JM Tavaré, F Lang

Research output: Contribution to journalArticle (Academic Journal)peer-review

15 Citations (Scopus)

Abstract

The cystic fibrosis transmembrane conductance regulator (CFTR) is a cAMP-activated Cl channel critically important in Cl secreting epithelia. Mutations in the CFTR gene, such as DF508CFTR leads to cystic fibrosis, a severe disease with defective Cl secretion. CFTR is stimulated by the serum and glucocorticoid- inducible kinase SGK1. The SGK1 dependent regulation of several carriers and channels involves the phosphatidylinositol-3-phosphate-5-kinase PIKfyve, which similarly mediates the regulation of glucose carriers by PKB/Akt. The present study was thus performed to elucidate whether PKB/Akt and PIKfyve are regulators of CFTR. To this end CFTR or DF508CFTR were expressed in Xenopus oocytes alone or together with PKB, PIKfyve or the SGK1/PKB resistant mutant S318APIKfyve, and the current generated by cAMP upregulation with 10 lM forskolin + 1 mM IBMX determined utilizing dual electrode voltage clamp. As a result, forskolin/IBMX treatment triggered a current (IcAMP) in CFTR-expressing Xenopus oocytes, but not in oocytes expressing DF508CFTR. Coexpression of PKB/Akt and PIKfyve, but not of S318APIKfyve, stimulated IcAMP in CFTR-expressing (2- to 3-fold) but not in DF508CFTR-expressing or water injected Xenopus oocytes. Immunohistochemistry revealed that the coexpression of PIKfyve, but not of S318APIKfyve, enhanced the CFTR protein abundance but not the DF508CFTR protein abundance in CFTR or DF508CFTR-expressing oocytes. The present observations reveal a novel powerful regulator of intact but not of defective CFTR.
Translated title of the contributionPIKfyve upregulates CFTR activity
Original languageEnglish
Pages (from-to)952 - 957
Number of pages6
JournalBiochemical and Biophysical Research Communications
Volume390 (3)
DOIs
Publication statusPublished - Dec 2009

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