Beyond the Mutations: Spatiotemporal Regulation of CFTR by cAMP and Calcium Signaling in Epithelial Physiology and Cystic Fibrosis

Varga, Árpád and Kiss, Aletta and Crul, Tim and Tamara, Madácsy and Pallagi, Petra and Maléth, József (2025) Beyond the Mutations: Spatiotemporal Regulation of CFTR by cAMP and Calcium Signaling in Epithelial Physiology and Cystic Fibrosis. Other. UNSPECIFIED. (Submitted)

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Abstract

Cystic fibrosis (CF) is a life-shortening monogenic disease caused by mutations in the CFTR gene, but the functional expression of the 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 cAMP/protein kinase A (PKA) pathway, which drives CFTR channel opening via phosphorylation of its regulatory (R) domain and coordination by scaffolding proteins (e.g. AKAPs and NHERF1). Equally important, Ca²⁺-dependent signaling cascades provide complementary fine-tuning: Ca²⁺-bound calmodulin can directly bind and increase CFTR open probability, Ca²⁺-activated kinases like CaMKII and the tyrosine kinase Pyk2 (with Src) can phosphorylate CFTR through non-canonical routes, and signaling intermediates such as 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.

Item Type:	Monograph (Other)
Subjects:	Q Science / természettudomány > QP Physiology / élettan R Medicine / orvostudomány > RZ Other systems of medicine / orvostudomány egyéb területei
Depositing User:	Dr. Tamara Madácsy
Date Deposited:	25 Sep 2025 06:36
Last Modified:	14 Oct 2025 15:41
URI:	https://real.mtak.hu/id/eprint/225171

Available Versions of this Item

• Beyond the Mutations: Spatiotemporal Regulation of CFTR by cAMP and Calcium Signaling in Epithelial Physiology and Cystic Fibrosis. (deposited 25 Sep 2025 06:36) [Currently Displayed]
  • Beyond the Mutations: Spatiotemporal Regulation of CFTR by cAMP and Calcium Signaling in Epithelial Physiology and Cystic Fibrosis. (deposited 29 Sep 2025 09:43)

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