The TRPV4 Agonist GSK1016790A Regulates the Membrane Expression of TRPV4 Channels

Frontiers in Pharmacology

Peter Thurgood²  Khashayar Khoshmanesh²  Peter McIntyre³  Parisa Vahidi³  Sara Baratchi³  William G. Darby³  Austin Lai³  Peter Keov⁴  Karin Ejendal⁵ 

[1] Molecular Pharmacology Division, Victor Chang Cardiac Research Institute, Darlinghurst, NSW, Australia;School of Engineering, RMIT University, Melbourne, VIC, Australia;School of Health and Biomedical Sciences, RMIT University, Melbourne, VIC, Australia;St Vincent's Clinical School, University of New South Wales, Darlinghurst, NSW, Australia;Weldon School of Biomedical Engineering, Purdue University, West Lafayette, IN, United States;

关键词: TRPV4;    membrane trafficking;    endothelial cells;    GSK1016790A;    calcium;   

DOI  :  10.3389/fphar.2019.00006

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown