The nonselective cation channel TRPV4 inhibits angiotensin II receptors

• Published in: The Journal of biological chemistry Vol. 295; no. 29; pp. 9986 - 9997
• Main Authors: Zaccor, Nicholas W., Sumner, Charlotte J., Snyder, Solomon H.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 17-07-2020; American Society for Biochemistry and Molecular Biology
• Subjects: angiotensin II receptor type 1 (AT1R); Animals; beta-arrestin; beta-Arrestins - genetics; beta-Arrestins - metabolism; calcineurin; Calcium - metabolism; Calmodulin - genetics; Calmodulin - metabolism; cell sensor; cell signaling; desensitization; Female; G-protein–coupled receptor (GPCR); HEK293 Cells; Humans; Male; Mice; phosphorylation; receptor desensitization; Receptors, Angiotensin - genetics; Receptors, Angiotensin - metabolism; Signal Transduction; transient receptor potential channels (TRP channels); transient receptor potential vanilloid 4 (TRPV4); TRPV Cation Channels - genetics; TRPV Cation Channels - metabolism; β-arrestin; transient receptor potential channels (TRP channels); transient receptor potential vanilloid 4 (TRPV4); β-arrestin; angiotensin II receptor type 1 (AT1R); G-protein–coupled receptor (GPCR); beta-arrestin; cell signaling; cell sensor; receptor desensitization; calcineurin; phosphorylation; desensitization
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.RA120.014325

G-protein–coupled receptors (GPCRs) are a ubiquitously expressed family of receptor proteins that regulate many physiological functions and other proteins. They act through two dissociable signaling pathways: the exchange of GDP to GTP by linked G-proteins and the recruitment of β-arrestins. GPCRs modulate several members of the transient receptor potential (TRP) channel family of nonselective cation channels. How TRP channels reciprocally regulate GPCR signaling is less well-explored. Here, using an array of biochemical approaches, including immunoprecipitation and fluorescence, calcium imaging, phosphate radiolabeling, and a β-arrestin–dependent luciferase assay, we characterize a GPCR–TRP channel pair, angiotensin II receptor type 1 (AT1R), and transient receptor potential vanilloid 4 (TRPV4), in primary murine choroid plexus epithelial cells and immortalized cell lines. We found that AT1R and TRPV4 are binding partners and that activation of AT1R by angiotensin II (ANGII) elicits β-arrestin–dependent inhibition and internalization of TRPV4. Activating TRPV4 with endogenous and synthetic agonists inhibited angiotensin II–mediated G-protein–associated second messenger accumulation, AT1R receptor phosphorylation, and β-arrestin recruitment. We also noted that TRPV4 inhibits AT1R phosphorylation by activating the calcium-activated phosphatase calcineurin in a Ca2+/calmodulin–dependent manner, preventing β-arrestin recruitment and receptor internalization. These findings suggest that when TRP channels and GPCRs are co-expressed in the same tissues, many of these channels can inhibit GPCR desensitization.