Abstract
| Original language | English |
|---|---|
| Article number | 6 |
| Number of pages | 12 |
| Journal | Frontiers in Pharmacology |
| Volume | 10 |
| DOIs | |
| Publication status | Published - 23 Jan 2019 |
Keywords
- TRPV4
- membrane trafficking
- endothelial cells
- GSK1016790A
- calcium
Cite this
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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 journal › Article › Research › peer-review
TY - JOUR
T1 - The TRPV4 Agonist GSK1016790A Regulates the Membrane Expression of TRPV4 Channels
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
PY - 2019/1/23
Y1 - 2019/1/23
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.
KW - TRPV4
KW - membrane trafficking
KW - endothelial cells
KW - GSK1016790A
KW - calcium
U2 - 10.3389/fphar.2019.00006
DO - 10.3389/fphar.2019.00006
M3 - Article
VL - 10
JO - Frontiers in Pharmacology
JF - Frontiers in Pharmacology
SN - 1663-9812
M1 - 6
ER -