Regulation of Channel Gating by AMP-activated Protein Kinase Modulates Cystic Fibrosis Transmembrane Conductance Regulator Activity in Lung Submucosal Cells

Hallows, Kenneth R.; McCane, Jill E.; Kemp, Bruce E.; Witters, Lee A.; Foskett, J. Kevin

doi:10.1074/jbc.m210621200

Cited by 102 publications

(99 citation statements)

References 39 publications

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“…The present results (see supplemental Fig. S1) also confirm those previous studies in that they demonstrate inhibition of the open probability of CFTR by phosphorylation through AMPK, rather than effects on membrane expression (6). The actions of AMPK are complex as this kinase regulates a number of transport proteins involved in secretion or absorption of electrolytes in epithelia.…”

Section: Discussionsupporting

confidence: 80%

“…Activation of AMPK in Xenopus oocytes by phenformin did not change the expression of CFTR in membranes of Xenopus oocytes (supplemental Fig. S1), confirming previous results indicating inhibition of the open probability of CFTR by AMPK (6).…”

Section: Cftr Is Inhibited By Baseline Activity Of Ampk-supporting

confidence: 79%

“…These kinases converge on the regulatory domain of CFTR that is unique not only within the large ABC transporter family but among all known sequences, and may be considered as a "phosphorylation control module" (3). Regulation of CFTR by an inhibitory kinase, the adenosine monophosphate-dependent kinase (AMPK), has been described recently but the regulatory sites within CFTR, the mechanism of regulation, and the physiological relevance have all remained obscure (5)(6)(7)(8). Additionally, CFTR mutation is linked to inflammation and a lack of functional CFTR expression has itself been suggested to up-regulate AMPK activity in epithelial cells carrying the cystic fibrosis (CF) defect.…”

mentioning

confidence: 99%

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Mechanistic Insight into Control of CFTR by AMPK

Kongsuphol

Cassidy

Hieke

et al. 2009

Journal of Biological Chemistry

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Section: Discussionsupporting

confidence: 80%

Section: Cftr Is Inhibited By Baseline Activity Of Ampk-supporting

confidence: 79%

mentioning

confidence: 99%

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Mechanistic Insight into Control of CFTR by AMPK

Kongsuphol

Cassidy

Hieke

et al. 2009

Journal of Biological Chemistry

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“…This model also includes a potential downstream effector, AMPK. This kinase is known to localize to the apical membrane (43), can down-regulate CFTR currents in Calu-3 cells (45), and may be stimulated by the locally increased 5Ј-AMP generated by PDE activity near the activated receptor/channel complex. Additional experiments will be required to elucidate the exact relationship between the 5Ј-AMP generated by PDE4 and AMPK activity in Calu-3 cells.…”

Section: Resultsmentioning

confidence: 99%

Phosphodiesterase 4D Forms a cAMP Diffusion Barrier at the Apical Membrane of the Airway Epithelium

Barnes

Livera

Huang

et al. 2005

Journal of Biological Chemistry

100

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We demonstrated previously that Calu-3 airway epithelial cells sense adenosine on their luminal surface through adenosine A2B receptors coupled to adenylyl cyclase. Occupancy of these receptors leads to activation of the cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel through protein kinase A (PKA) anchored at the apical membrane. Because luminal A2B receptor activation does not raise total cellular cAMP levels, we hypothesized that activation of phosphodiesterases (PDEs) confines cAMP generated by apical A2B receptors to a microdomain that includes the CFTR channel. Using reverse transcription-PCR, Western blotting, and activity measurements, PDE4D was identified as the major PDE species in airway epithelia. Consistent with these results, inhibitors of PDE4, but not PDE3, selectively abolished the lateral confinement of cAMP signaling in apical membrane patches during cell-attached recordings. Furthermore, stimulation of the CFTR in excised apical patches by rolipram and RS25344 indicated that PDE4 is localized in close proximity to the CFTR channel. Indeed, immunohistochemistry of human airway sections revealed that PDE4D is localized in the apical domain of the cell. PDE4 was activated after luminal adenosine exposure in a PKA-dependent manner. Because PDE4 activity is positively regulated by PKA, our results support a model whereby the PDE diffusion barrier is proportional to the degree of receptor stimulation. These findings underscore the concept that subcellular localization of individual PDE isozymes is an important mechanism for confining cAMP signaling to functional domains within cells.

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“…On the other hand, it has recently been shown that a metabolic sensor AMPK inhibits CFTR function in heterologous expression systems, polarized epithelial cells and mouse intestine. [8][9][10][11] Recent studies demonstrated that AMPK phosphorylates at serine 737 and serine 768 in the R domain, resulting in inhibition of both basal and PKA-stimulated CFTR activities. 12) Stevioside is a natural sweetener extracted from Stevia rebaudiana.…”

Section: Cystic Fibrosis Transmembrane Conductance Regulator (Cftr) Imentioning

confidence: 99%

Activation of AMP-Activated Protein Kinase by a Plant-Derived Dihydroisosteviol in Human Intestinal Epithelial Cell

Muanprasat

Sirianant

Sawasvirojwong

et al. 2013

Biological & Pharmaceutical Bulletin

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Our previous study has shown that dihydroisosteviol (DHIS), a derivative of stevioside isolated from Stevia rebaudiana (Bertoni), inhibits cystic fibrosis transmembrane conductance regulator (CFTR)-mediated transepithelial chloride secretion across monolayers of human intestinal epithelial (T84) cells and prevents cholera toxin-induced intestinal fluid secretion in mouse closed loop models. In this study, we aimed to investigate a mechanism by which DHIS inhibits CFTR activity. Apical chloride current measurements in Fisher rat thyroid cells stably transfected with wild-type human CFTR (FRT-CFTR cells) and T84 cells were used to investigate mechanism of CFTR inhibition by DHIS. In addition, effect of DHIS on AMP-activated protein kinase (AMPK) activation was investigated using Western blot analysis. Surprisingly, it was found that DHIS failed to inhibit CFTR-mediated apical chloride current in FRT-CFTR cells. In contrast, DHIS effectively inhibited CFTR-mediated apical chloride current induced by a cell permeable cAMP analog CPT-cAMP and a direct CFTR activator genistein in T84 cell monolayers. Interestingly, this inhibitory effect of DHIS on CFTR was significantly (p<0.05) reduced by pretreatment with compound C, an AMPK inhibitor. AICAR, a known AMPK activator, was able to inhibit CFTR activity in both FRT-CFTR and T84 cells. Western blot analysis showed that DHIS induced AMPK activation in T84 cells, but not in FRT-CFTR cells. Our results indicate that DHIS inhibits CFTR-mediated chloride secretion in T84 cells, in part, by activation of AMPK activity. DHIS therefore represents a novel candidate of AMPK activators.

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Regulation of Channel Gating by AMP-activated Protein Kinase Modulates Cystic Fibrosis Transmembrane Conductance Regulator Activity in Lung Submucosal Cells

Cited by 102 publications

References 39 publications

Mechanistic Insight into Control of CFTR by AMPK

Mechanistic Insight into Control of CFTR by AMPK

Phosphodiesterase 4D Forms a cAMP Diffusion Barrier at the Apical Membrane of the Airway Epithelium

Activation of AMP-Activated Protein Kinase by a Plant-Derived Dihydroisosteviol in Human Intestinal Epithelial Cell

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