Potential sites of CFTR activation by tyrosine kinases

Billet, Arnaud; Jia, Yanlin; Jensen, Timothy J.; Hou, Yue Xian; Chang, Xiu Bao; Riordan, John R.; Hanrahan, John W.

doi:10.1080/19336950.2015.1126010

Cited by 14 publications

(6 citation statements)

References 19 publications

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“…CFTR can be regulated by multiple enzymes (Dahan et al 2001), including protein kinase C (Jia et al 1997), some tyrosine kinases (Billet et al 2016), and AMP-dependent protein kinase (Hallows et al 2000), as well as phosphatases (Luo et al 1998). At the most fundamental level, however, CFTR activity is dependent on ATP binding and hydrolysis and is substantially enhanced by phosphorylation via protein kinase A (PKA).…”

Section: Discussionmentioning

confidence: 99%

A role for the cystic fibrosis transmembrane conductance regulator in the nitric oxide-dependent release of Cl⁻ from acidic organelles in amacrine cells

Krishnan

Maddox

Rodriguez

et al. 2017

Journal of Neurophysiology

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γ-Amino butyric acid (GABA) and glycine typically mediate synaptic inhibition because their ligand-gated ion channels support the influx of Cl However, the electrochemical gradient for Cl across the postsynaptic plasma membrane determines the voltage response of the postsynaptic cell. Typically, low cytosolic Cl levels support inhibition, whereas higher levels of cytosolic Cl can suppress inhibition or promote depolarization. We previously reported that nitric oxide (NO) releases Cl from acidic organelles and transiently elevates cytosolic Cl, making the response to GABA and glycine excitatory. In this study, we test the hypothesis that the cystic fibrosis transmembrane conductance regulator (CFTR) is involved in the NO-dependent efflux of organellar Cl We first establish the mRNA and protein expression of CFTR in our model system, cultured chick retinal amacrine cells. Using whole cell voltage-clamp recordings of currents through GABA-gated Cl channels, we examine the effects of pharmacological inhibition of CFTR on the NO-dependent release of internal Cl To interfere with the expression of CFTR, we used clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 genome editing. We find that both pharmacological inhibition and CRISPR/Cas9-mediated knockdown of CFTR block the ability of NO to release Cl from internal stores. These results demonstrate that CFTR is required for the NO-dependent efflux of Cl from acidic organelles. Although CFTR function has been studied extensively in the context of epithelia, relatively little is known about its function in neurons. We show that CFTR is involved in an NO-dependent release of Cl from acidic organelles. This internal function of CFTR is particularly relevant to neuronal physiology because postsynaptic cytosolic Cl levels determine the outcome of GABA- and glycinergic synaptic signaling. Thus the CFTR may play a role in regulating synaptic transmission.

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Section: Discussionmentioning

confidence: 99%

A role for the cystic fibrosis transmembrane conductance regulator in the nitric oxide-dependent release of Cl⁻ from acidic organelles in amacrine cells

Krishnan

Maddox

Rodriguez

et al. 2017

Journal of Neurophysiology

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“…Considering the essential role of PKA-dependent phosphorylation of the intrinsically disordered R domain in modulating CFTR gating ( Hallows et al, 2003 ; Billet et al, 2015 , 2016 ), it is plausible that CF-causing mutations may disturb this mechanism of channel regulation. The most common CFTR mutation, consisting of the deletion of phenylalanine (F508del) located at the interface between NBD1 and the intracellular loop 4, interferes with the correct R domain folding and assembly ( Riordan, 2005 ; Hwang et al, 2018 ).…”

Section: Effects Of Cf-causing Mutations On Pka-mediated Phosphorylation Of Cftrmentioning

confidence: 99%

Role of Protein Kinase A-Mediated Phosphorylation in CFTR Channel Activity Regulation

Sala

Prono²,

Hirsch

et al. 2021

Front. Physiol.

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Cystic fibrosis transmembrane conductance regulator (CFTR) is an anion channel expressed on the apical membrane of epithelial cells, where it plays a pivotal role in chloride transport and overall tissue homeostasis. CFTR constitutes a unique member of the ATP-binding cassette transporter superfamily, due to its distinctive cytosolic regulatory (R) domain carrying multiple phosphorylation sites that allow the tight regulation of channel activity and gating. Mutations in the CFTR gene cause cystic fibrosis, the most common lethal autosomal genetic disease in the Caucasian population. In recent years, major efforts have led to the development of CFTR modulators, small molecules targeting the underlying genetic defect of CF and ultimately rescuing the function of the mutant channel. Recent evidence has highlighted that this class of drugs could also impact on the phosphorylation of the R domain of the channel by protein kinase A (PKA), a key regulatory mechanism that is altered in various CFTR mutants. Therefore, the aim of this review is to summarize the current knowledge on the regulation of the CFTR by PKA-mediated phosphorylation and to provide insights into the different factors that modulate this essential CFTR modification. Finally, the discussion will focus on the impact of CF mutations on PKA-mediated CFTR regulation, as well as on how small molecule CFTR regulators and PKA interact to rescue dysfunctional channels.

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“…This primarily involves PKA, but other kinases are known to phosphorylate CFTR leading to either its activation (e.g. cGMP-dependent protein kinase, Src and proline-rich tyrosine kinase Pyk2 [19,20]) or inhibition (e.g. AMP-dependent protein kinase -AMPK) [21], with some having a dual role in channel activity (e.g.…”

Section: Membrane Functionfrom Internal To External Regulatorsmentioning

confidence: 99%

Protein and lipid interactions – Modulating CFTR trafficking and rescue

Farinha

Miller

McCarty

2018

Journal of Cystic Fibrosis

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Different levels of CFTR regulation in the cell contribute to a stringent control of chloride secretion in epithelia. Tuning of chloride transport is achieved by modulating CFTR biogenesis, exit from the endoplasmic reticulum, trafficking, membrane stability and channel activity. In this short review, we summarize recent findings identifying interactions with other proteins - directly or through membrane lipids - and briefly discuss how these observations can provide clues to the design of better therapeutic approaches.

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Potential sites of CFTR activation by tyrosine kinases

Cited by 14 publications

References 19 publications

A role for the cystic fibrosis transmembrane conductance regulator in the nitric oxide-dependent release of Cl⁻ from acidic organelles in amacrine cells

A role for the cystic fibrosis transmembrane conductance regulator in the nitric oxide-dependent release of Cl⁻ from acidic organelles in amacrine cells

Role of Protein Kinase A-Mediated Phosphorylation in CFTR Channel Activity Regulation

Protein and lipid interactions – Modulating CFTR trafficking and rescue

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Potential sites of CFTR activation by tyrosine kinases

Cited by 14 publications

References 19 publications

A role for the cystic fibrosis transmembrane conductance regulator in the nitric oxide-dependent release of Cl− from acidic organelles in amacrine cells

A role for the cystic fibrosis transmembrane conductance regulator in the nitric oxide-dependent release of Cl− from acidic organelles in amacrine cells

Role of Protein Kinase A-Mediated Phosphorylation in CFTR Channel Activity Regulation

Protein and lipid interactions – Modulating CFTR trafficking and rescue

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Product

Resources

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A role for the cystic fibrosis transmembrane conductance regulator in the nitric oxide-dependent release of Cl⁻ from acidic organelles in amacrine cells

A role for the cystic fibrosis transmembrane conductance regulator in the nitric oxide-dependent release of Cl⁻ from acidic organelles in amacrine cells