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MBC in Press, published online ahead of print June 20, 2007
Mol. Biol. Cell 10.1091/mbc.E07-02-0126

A more recent version of this article appeared on September 1, 2007
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Submitted on February 20, 2007
Revised on June 6, 2007
Accepted on June 11, 2007

The Formation of the cAMP/PKA-dependent Annexin 2-S100A10 Complex with CFTR Regulates CFTR Channel Function

Lee A. Borthwick,* Jean Mcgaw,* Gregory Conner,{dagger} Christopher J. Taylor,* Volker Gerke,{ddagger} Anil Mehta,{sect} Louise Robson,|| and Richmond Muimo*

*Academic Unit of Child Health, The University of Sheffield, Sheffield Children’s Hospital, Sheffield, S10 2TH, United Kingdom; ||Department of Biomedical Science, The University of Sheffield, Western Bank, Sheffield S10 2TN, United Kingdom; {dagger}Division of Pulmonary and Critical Care Medicine, Department of Cell Biology and Anatomy, University of Miami School of Medicine, Miami, FL 33101; {ddagger}Institute of Medical Biochemistry, University of Münster, D-48149 Münster, Germany; {sect}Tayside Institute of Child Health, Ninewells Hospital and Medical School, University of Dundee, DD1 9SY, United Kingdom

Monitoring Editor: Jeffrey Brodsky

Cystic fibrosis results from mutations in the cystic fibrosis conductance regulator protein (CFTR), a cAMP/PKA and ATP-regulated Cl- channel. CFTR is increasingly recognized as a component of multi-protein complexes and although several inhibitory proteins to CFTR have been identified, protein complexes that stimulate CFTR function remain less well characterized. We report that annexin 2 (anx 2)-S100A10 forms a functional cAMP/PKA/calcineurin (CaN)-dependent complex with CFTR. Cell stimulation with FSK/IBMX significantly increases the amount of anx 2-S100A10 that reciprocally coimmunoprecipitates with cell surface CFTR and CaN A. Pre-inhibition with PKA or CaN inhibitors attenuates the interaction. Furthermore, we find that the acetylated peptide (STVHEILCKLSLEG, Ac1-14), but not the nonacetylated equivalent N1-14, corresponding to the S100A10 binding site on anx 2, disrupts the anx 2-S100A10/CFTR complex. Analysis of DIDS and CFTRinh172-sensitive currents, taken as indication of the outwardly rectifying Cl- channels (ORCC) and CFTR-mediated currents, respectively, showed that Ac1-14, but not N1-14, inhibits both the cAMP/PKA-dependent ORCC and CFTR activities. CaN inhibitors (cypermethrin, cyclosporin A) discriminated between ORCC/CFTR by inhibiting the CFTRinh172-, but not the DIDS, sensitive currents, by more than 70%. Furthermore, peptide Ac1-14 inhibited acetylcholine-induced short-circuit current measured across a sheet of intact intestinal biopsy. Our data suggests that the anx 2-S100A10/CFTR complex is important for CFTR function across epithelia.

Address correspondence to: Richmond Muimo (r.muimo{at}sheffield.ac.uk)






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