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Mouse Cftr/Abcc7 is an ABC transporter superfamily (ABCC subfamily) member but,
unusually, functions primarily as a regulated anion channel rather than a classical
active transporter; its ATPase activity gates channel opening.
"CFTR (mouse **Cftr/Abcc7**) is a member of the **ATP-binding cassette (ABC) transporter superfamily (ABCC subfamily)** but is unusual in that it functions primarily as a **regulated anion channel** rather than a classical active transporter."
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The primary molecular function of CFTR is to conduct chloride and bicarbonate anions
across epithelial plasma membranes down electrochemical gradients, driving fluid and
electrolyte transport and regulating pH.
"The primary function of CFTR is to conduct **anions**, especially **chloride (Cl−)** and **bicarbonate (HCO3−)**, across epithelial plasma membranes down electrochemical gradients to drive fluid and electrolyte transport and regulate pH."
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CFTR domain architecture comprises two membrane-spanning domains (12 TM helices total),
two cytosolic nucleotide-binding domains (NBD1, NBD2), and a regulatory R domain enriched
in phosphorylation sites.
"two cytosolic **nucleotide-binding domains** (**NBD1, NBD2**), and a regulatory **R domain** enriched in phosphorylation sites."
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Channel gating requires phosphorylation of the R domain (typically via cAMP/PKA signaling)
together with ATP binding and NBD dimerization to open the channel; ATP hydrolysis at site 2
promotes closure via NBD dimer dissociation.
"CFTR activity requires (i) **phosphorylation of the R domain** (typically via **cAMP/PKA signaling**; intestinal-specific PKG contributions are also described) and (ii) **ATP binding and NBD dimerization** to open the channel, with **ATP hydrolysis at site 2** promoting closure (dissociation of the NBD dimer)."
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CFTR is predominantly localized to the apical plasma membrane of polarized epithelial cells,
including airway, intestinal, pancreatic duct, sweat duct, and reproductive tract epithelia.
"CFTR is predominantly localized to the **apical plasma membrane** of polarized epithelial cells, including airway, intestinal, pancreatic duct, sweat duct, and reproductive tract epithelia."
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CFTR-mediated anion secretion is integrated with basolateral NKCC1, Na+/K+-ATPase, and K+
channels, and bicarbonate handling via SLC26A3 (DRA) and SLC26A6 (PAT-1) exchangers and
NBC transporters.
"**HCO3−** supply/handling involves Na+-coupled transporters (NBCe1/NBCn1) and luminal/basolateral exchangers including **SLC26A3 (DRA)** and **SLC26A6 (PAT-1)**, functionally integrated with CFTR."
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Mouse-specific signaling evidence includes a direct CFTR-AC6 interaction in mouse intestinal
mucosa/colon epithelial cells, with failure of forskolin-induced swelling in AC6-deficient
mouse intestinal organoids, supporting AC6's role in CFTR-dependent secretion.
"Mouse-specific evidence described includes **direct CFTR–AC6 interaction in mouse intestinal mucosa/colon epithelial cells** and failure of forskolin-induced swelling in intestinal organoids derived from **AC6-deficient mice**, supporting AC6's role in CFTR-dependent secretion."
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A 2024 cryo-EM study showed PKA catalytic subunit (PKA-C) binding alone can stimulate CFTR
currents (noncatalytic, phosphorylation-independent potentiation), with PKA-C docking at two
catalytic stations on CFTR.
"PKA-C binding alone can stimulate CFTR currents ("noncatalytic activation")."