02922nab a2200277 i 4500 publ38954 20260204094112.0 260204s2026 hu o 000 eng d 1425-8153 10.1186/s11658-025-00836-1 doi 36750739 mtmt SZTE Publicatio Repozitórium hun eng Varga Árpád Beyond the mutations [elektronikus dokumentum] : spatiotemporal regulation of CFTR by cAMP and calcium signaling in epithelial physiology and cystic fibrosis / Varga Árpád 2026 31 CELLULAR AND MOLECULAR BIOLOGY LETTERS 31 No. 1 Cystic fibrosis (CF) is a life-shortening monogenic disease caused by mutations in the CFTR gene, but the functional expression of the cystic fibrosis transmembrane conductance regulator (CFTR) Cl-/HCO3- channel is determined by more than its genetic sequence. Beyond the well-known folding defect of the common F508del mutation, CFTR activity is dynamically modulated by a network of intracellular signaling pathways that control the channel's gating, trafficking to, and retention at the apical membrane. Foremost is the cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA) pathway, which drives CFTR opening via phosphorylation of its regulatory (R) domain and coordination by scaffolding proteins (e.g., A-kinase anchoring proteins (AKAPs) and Na+/H+ exchanger regulatory factor 1 (NHERF1)). Equally important, Ca2+-dependent signaling cascades provide complementary fine-tuning: Ca2+-bound calmodulin can directly bind and increase the CFTR open probability, Ca2+-activated kinases such as Ca2+/calmodulin-dependent protein kinase II (CaMKII) and the tyrosine kinase Pyk2 (with Src) can phosphorylate CFTR through noncanonical routes, and signaling intermediates such as IP3 receptor binding protein released with IP3(IRBIT) connect Ca2+ release to CFTR activation. These cAMP- and Ca2+-driven pathways intersect in specialized subcellular nanodomains, enabling precise spatiotemporal regulation of CFTR function. Clinically, although new CFTR modulator drugs have greatly improved outcomes, their effectiveness is limited by mutation-specific responses and incomplete restoration of channel activity. Understanding how cAMP-Ca2+ crosstalk governs CFTR in context can reveal novel therapeutic strategies targeting the channel's regulatory microenvironment. This review highlights how compartmentalized cAMP and Ca2+ signals orchestrate CFTR function and discusses emerging approaches to harness this insight for better therapies across CF-affected organs. Klinikai orvostan Kiss Aletta Kata aut Crul Tim aut Madácsy Tamara aut Pallagi Petra aut Maléth József aut http://publicatio.bibl.u-szeged.hu/38954/1/Varga.pdf Dokumentum-elérés