The mechano-sensitivity of cardiac ATP-sensitive potassium channels is mediated by intrinsic MgATPase activity

Fatehi, Mohammad; Carter, Christian C.; Youssef, Nermeen; Light, Peter E.

doi:10.1016/j.yjmcc.2017.05.004

Cited by 8 publications

(7 citation statements)

References 43 publications

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“…However this bilayer tension can be regulated by the actin cytoskeleton (231). This sensitivity was dependent on the SUR subunit and in particular nucleotide handling in NBD2 (135): specifically mutation of a residue (K1337) abolished the effect.…”

Section: Mechanosensitivity Of K Atp Channelsmentioning

confidence: 99%

ATP‐Sensitive Potassium Channels and Their Physiological and Pathophysiological Roles

Tinker

Aziz

et al. 2018

Comprehensive Physiology

111

112

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ATP sensitive potassium channels (K ) are so named because they open as cellular ATP levels fall. This leads to membrane hyperpolarization and thus links cellular metabolism to membrane excitability. They also respond to MgADP and are regulated by a number of cell signaling pathways. They have a rich and diverse pharmacology with a number of agents acting as specific inhibitors and activators. K channels are formed of pore-forming subunits, Kir6.1 and Kir6.2, and a large auxiliary subunit, the sulfonylurea receptor (SUR1, SUR2A, and SUR2B). The Kir6.0 subunits are a member of the inwardly rectifying family of potassium channels and the sulfonylurea receptor is part of the ATP-binding cassette family of proteins. Four SURs and four Kir6.x form an octameric channel complex and the association of a particular SUR with a specific Kir6.x subunit constitutes the K current in a particular tissue. A combination of mutagenesis work combined with structural studies has identified how these channels work as molecular machines. They have a variety of physiological roles including controlling the release of insulin from pancreatic β cells and regulating blood vessel tone and blood pressure. Furthermore, mutations in the genes underlie human diseases such as congenital diabetes and hyperinsulinism. Additionally, opening of these channels is protective in a number of pathological conditions such as myocardial ischemia and stroke. © 2018 American Physiological Society. Compr Physiol 8:1463-1511, 2018.

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Section: Mechanosensitivity Of K Atp Channelsmentioning

confidence: 99%

ATP‐Sensitive Potassium Channels and Their Physiological and Pathophysiological Roles

Tinker

Aziz

et al. 2018

Comprehensive Physiology

111

112

View full text Add to dashboard Cite

show abstract

“…Patch‐clamp recordings were carried out as we described previously (Fatehi et al., 2017), under voltage clamp at room temperature (∼22°C). The recording pipette and chamber were coupled by Ag/AgCl electrodes to an Axopatch 200B patch‐clamp amplifier and Digidata 1200A BNC data‐acquisition system, controlled by pCLAMP 10 software (Axon Instruments).…”

Section: Methodsmentioning

confidence: 99%

Regulation of PKD2 channel function by TACAN

Liu

Zhang

Fatehi

et al. 2022

The Journal of Physiology

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Autosomal dominant polycystic kidney disease is caused by mutations in the membrane receptor PKD1 or the cation channel PKD2. TACAN (also termed TMEM120A), recently reported as an ion channel in neurons for mechanosensing and pain sensing, is also distributed in diverse non‐neuronal tissues, such as kidney, heart and intestine, suggesting its involvement in other functions. In this study, we found that TACAN is in a complex with PKD2 in native renal cell lines. Using the two‐electrode voltage clamp in Xenopus oocytes, we found that TACAN inhibits the channel activity of PKD2 gain‐of‐function mutant F604P. TACAN fragments containing the first and last transmembrane domains interacted with the PKD2 C‐ and N‐terminal fragments, respectively. The TACAN N‐terminus acted as a blocking peptide, and TACAN inhibited the function of PKD2 by the binding of PKD2 with TACAN. By patch clamping in mammalian cells, we found that TACAN inhibits both the single‐channel conductance and the open probability of PKD2 and mutant F604P. PKD2 co‐expressed with TACAN, but not PKD2 alone, exhibited pressure sensitivity. Furthermore, we found that TACAN aggravates PKD2‐dependent tail curvature and pronephric cysts in larval zebrafish. In summary, this study revealed that TACAN acts as a PKD2 inhibitor and mediates mechanosensitivity of the PKD2–TACAN channel complex. Key points TACAN inhibits the function of PKD2 in vitro and in vivo. TACAN N‐terminal S1‐containing fragment T160X interacts with the PKD2 C‐terminal fragment N580–L700, and its C‐terminal S6‐containing fragment L296–D343 interacts with the PKD2 N‐terminal A594X. TACAN inhibits the function of the PKD2 channel by physical interaction. The complex of PKD2 with TACAN, but not PKD2 alone, confers mechanosensitivity.

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“…Patch-clamp recordings were carried out as we described previously (Fatehi et al, 2017), under voltage clamp at room temperature (~22°C). The recording pipette and chamber were coupled by Ag/AgCl electrodes to an Axopatch 200B patch-clamp amplifier and Digidata 1200A BNC data-acquisition system, controlled by pCLAMP 10 software (Axon Instruments).…”

Section: Methodsmentioning

confidence: 99%

Regulation of the PKD2 Channel Function by TACAN

Liu

Zhang

Fatehi

et al. 2021

Preprint

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Autosomal dominant polycystic kidney disease (ADPKD) is caused by mutations in membrane receptor PKD1 or cation channel PKD2. TACAN (also named TMEM120A), recently reported as an ion channel in neuron cells for mechano and pain sensing, is also distributed in diverse non-neuronal tissues such as kidney, heart and intestine, suggesting its involvement in other functions. In this study, we found that TACAN is in complex with PKD2 in native renal cell lines. Using the two-electrode voltage clamp in Xenopus oocytes we found that TACAN inhibited the channel activity of PKD2 gain-of-function mutant F604P. The first and last transmembrane domains of TACAN were found to interact with the PKD2 C- and N-terminal portions, respectively. We showed that the TACAN N-terminus acted as a blocking peptide and that TACAN inhibits the PKD2 function through the PKD2/TACAN binding. By patch clamping in mammalian cells, we found that TACAN inhibits both the single channel conductance and open probability of PKD2 and mutant F604P. Further, PKD2 co-expressed with TACAN, but not PKD2 alone, exhibited pressure sensitivity. In summary, this study revealed that TACAN acts as a PKD2 inhibitor and mediates mechano sensitivity of the PKD2/TACAN channel complex.

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The mechano-sensitivity of cardiac ATP-sensitive potassium channels is mediated by intrinsic MgATPase activity

Cited by 8 publications

References 43 publications

ATP‐Sensitive Potassium Channels and Their Physiological and Pathophysiological Roles

ATP‐Sensitive Potassium Channels and Their Physiological and Pathophysiological Roles

Regulation of PKD2 channel function by TACAN

Regulation of the PKD2 Channel Function by TACAN

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