The TRPV4 Agonist GSK1016790A Regulates the Membrane Expression of TRPV4 Channels

Sara Baratchi, Peter Keov, William Darby, Austin Lai, Khashayar Khoshmanesh, Peter Thurgood, Parisa Vahidi, Karin Ejendal, Peter McIntyre

Research output: Contribution to journalArticleResearchpeer-review

Abstract

TRPV4 is a non-selective cation channel that tunes the function of different tissues including the vascular endothelium, lung, chondrocytes, and neurons. GSK1016790A is the selective and potent agonist of TRPV4 and a pharmacological tool that is used to study the TRPV4 physiological function in vitro and in vivo. It remains unknown how the sensitivity of TRPV4 to this agonist is regulated. The spatial and temporal dynamics of receptors are the major determinants of cellular responses to stimuli. Membrane translocation has been shown to control the response of several members of the transient receptor potential (TRP) family of ion channels to different stimuli. Here, we show that TRPV4 stimulation with GSK1016790A caused an increase in [Ca2+]i that is stable for a few minutes. Single molecule analysis of TRPV4 channels showed that the density of TRPV4 at the plasma membrane is controlled through two modes of membrane trafficking, complete, and partial vesicular fusion. Further, we show that the density of TRPV4 at the plasma membrane decreased within 20 min, as they translocate to the recycling endosomes and that the surface density is dependent on the release of calcium from the intracellular stores and is controlled via a PI3K, PKC, and RhoA signaling pathway.
Original languageEnglish
Article number6
Number of pages12
JournalFrontiers in Pharmacology
Volume10
DOIs
Publication statusPublished - 23 Jan 2019

Keywords

  • TRPV4
  • membrane trafficking
  • endothelial cells
  • GSK1016790A
  • calcium

Cite this

Baratchi, Sara ; Keov, Peter ; Darby, William ; Lai, Austin ; Khoshmanesh, Khashayar ; Thurgood, Peter ; Vahidi, Parisa ; Ejendal, Karin ; McIntyre, Peter. / The TRPV4 Agonist GSK1016790A Regulates the Membrane Expression of TRPV4 Channels. In: Frontiers in Pharmacology. 2019 ; Vol. 10.
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abstract = "TRPV4 is a non-selective cation channel that tunes the function of different tissues including the vascular endothelium, lung, chondrocytes, and neurons. GSK1016790A is the selective and potent agonist of TRPV4 and a pharmacological tool that is used to study the TRPV4 physiological function in vitro and in vivo. It remains unknown how the sensitivity of TRPV4 to this agonist is regulated. The spatial and temporal dynamics of receptors are the major determinants of cellular responses to stimuli. Membrane translocation has been shown to control the response of several members of the transient receptor potential (TRP) family of ion channels to different stimuli. Here, we show that TRPV4 stimulation with GSK1016790A caused an increase in [Ca2+]i that is stable for a few minutes. Single molecule analysis of TRPV4 channels showed that the density of TRPV4 at the plasma membrane is controlled through two modes of membrane trafficking, complete, and partial vesicular fusion. Further, we show that the density of TRPV4 at the plasma membrane decreased within 20 min, as they translocate to the recycling endosomes and that the surface density is dependent on the release of calcium from the intracellular stores and is controlled via a PI3K, PKC, and RhoA signaling pathway.",
keywords = "TRPV4, membrane trafficking, endothelial cells, GSK1016790A, calcium",
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Baratchi, S, Keov, P, Darby, W, Lai, A, Khoshmanesh, K, Thurgood, P, Vahidi, P, Ejendal, K & McIntyre, P 2019, 'The TRPV4 Agonist GSK1016790A Regulates the Membrane Expression of TRPV4 Channels' Frontiers in Pharmacology, vol. 10, 6. https://doi.org/10.3389/fphar.2019.00006

The TRPV4 Agonist GSK1016790A Regulates the Membrane Expression of TRPV4 Channels. / Baratchi, Sara; Keov, Peter; Darby, William; Lai, Austin; Khoshmanesh, Khashayar; Thurgood, Peter; Vahidi, Parisa; Ejendal, Karin; McIntyre, Peter.

In: Frontiers in Pharmacology, Vol. 10, 6, 23.01.2019.

Research output: Contribution to journalArticleResearchpeer-review

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AU - Baratchi, Sara

AU - Keov, Peter

AU - Darby, William

AU - Lai, Austin

AU - Khoshmanesh, Khashayar

AU - Thurgood, Peter

AU - Vahidi, Parisa

AU - Ejendal, Karin

AU - McIntyre, Peter

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N2 - TRPV4 is a non-selective cation channel that tunes the function of different tissues including the vascular endothelium, lung, chondrocytes, and neurons. GSK1016790A is the selective and potent agonist of TRPV4 and a pharmacological tool that is used to study the TRPV4 physiological function in vitro and in vivo. It remains unknown how the sensitivity of TRPV4 to this agonist is regulated. The spatial and temporal dynamics of receptors are the major determinants of cellular responses to stimuli. Membrane translocation has been shown to control the response of several members of the transient receptor potential (TRP) family of ion channels to different stimuli. Here, we show that TRPV4 stimulation with GSK1016790A caused an increase in [Ca2+]i that is stable for a few minutes. Single molecule analysis of TRPV4 channels showed that the density of TRPV4 at the plasma membrane is controlled through two modes of membrane trafficking, complete, and partial vesicular fusion. Further, we show that the density of TRPV4 at the plasma membrane decreased within 20 min, as they translocate to the recycling endosomes and that the surface density is dependent on the release of calcium from the intracellular stores and is controlled via a PI3K, PKC, and RhoA signaling pathway.

AB - TRPV4 is a non-selective cation channel that tunes the function of different tissues including the vascular endothelium, lung, chondrocytes, and neurons. GSK1016790A is the selective and potent agonist of TRPV4 and a pharmacological tool that is used to study the TRPV4 physiological function in vitro and in vivo. It remains unknown how the sensitivity of TRPV4 to this agonist is regulated. The spatial and temporal dynamics of receptors are the major determinants of cellular responses to stimuli. Membrane translocation has been shown to control the response of several members of the transient receptor potential (TRP) family of ion channels to different stimuli. Here, we show that TRPV4 stimulation with GSK1016790A caused an increase in [Ca2+]i that is stable for a few minutes. Single molecule analysis of TRPV4 channels showed that the density of TRPV4 at the plasma membrane is controlled through two modes of membrane trafficking, complete, and partial vesicular fusion. Further, we show that the density of TRPV4 at the plasma membrane decreased within 20 min, as they translocate to the recycling endosomes and that the surface density is dependent on the release of calcium from the intracellular stores and is controlled via a PI3K, PKC, and RhoA signaling pathway.

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JO - Frontiers in Pharmacology

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SN - 1663-9812

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ER -