Arrestin-biased AT1R agonism induces acute catecholamine secretion through TRPC3 coupling

Abstract

Acute hormone secretion triggered by G protein-coupled receptor (GPCR) activation underlies many fundamental physiological processes. GPCR signalling is negatively regulated by β-arrestins, adaptor molecules that also activate different intracellular signalling pathways. Here we reveal that TRV120027, a β-arrestin-1-biased agonist of the angiotensin II receptor type 1 (AT1R), stimulates acute catecholamine secretion through coupling with the transient receptor potential cation channel subfamily C 3 (TRPC3). We show that TRV120027 promotes the recruitment of TRPC3 or phosphoinositide-specific phospholipase C (PLCγ) to the AT1R-β-arrestin-1 signalling complex. Replacing the C-terminal region of β-arrestin-1 with its counterpart on β-arrestin-2 or using a specific TAT-P1 peptide to block the interaction between β-arrestin-1 and PLCγ abolishes TRV120027-induced TRPC3 activation. Taken together, our results show that the GPCR-arrestin complex initiates non-desensitized signalling at the plasma membrane by coupling with ion channels. This fast communication pathway might be a common mechanism of several cellular processes.

β-arrestin-1: Bridging GPCRs to active TRP channels

“…Surprisingly, unlike the notion that the activation of Gq-PLCb mediates secretion through IP3R sensitive intracellular Ca 2C store, the b-arrestin-1-dependent mechanism is specifically and critically dependent on the extracellular Ca 2C influx through the plasma membrane. Liu et al 5 then screened a series of channel blockers and found that the AT1R-b-arrestin-1-mediated Ca 2C influx was through TRPC3 at the plasma membrane, which was confirmed by using the TRPC3 ¡/¡ /TRPC6 ¡/ ¡ /TRPC7 ¡/¡ mice. The activation of TRP channels by GPCRs has been reported previously, but they are mainly dependent on G protein signal pathways, leading to changes in the membrane expression and/or activation threshold of TRP channels.…”

“…The activation of TRP channels by GPCRs has been reported previously, but they are mainly dependent on G protein signal pathways, leading to changes in the membrane expression and/or activation threshold of TRP channels. [1][2][3]5,7 The finding that AT1R-b-arrestin-1 specifically activates TRPC3 is interesting and totally different from the canonical Gq-PLCb pathway that often shows a nonselective modulation of several distinct TRP channels. 1,2 Since b-arrestin-1 may mediate coupling of AT1R and TRPC3 by a direct functional complex formation or through an indirect cascade signaling pathway, Liu et al 5 thus performed co-immunoprecipitations, bioluminescence resonance energy transfer experiments, and patch clamp recordings.…”

“…2,7 TRP channels cannot only be directly activated by various chemical, mechanical and thermal stimuli, but also function as major effectors of GPCRs downstream of G protein-dependent signal transduction pathways. [1][2][3]8 In this highlighted study, Liu and colleagues 5 unexpectedly identified a new b-arrestin-1-mediated, G protein-independent, fast communication between GPCR and TRPC3, which substantially contributes to acute catecholamine secretion following AT1R activation. 5 With the specific G protein or b-arrestin-1 biased AT1R agonists and knockout mice models, Liu et al 5 found that not only the Gq-PLCb-mediated pathway but also b-arrestin-1-biased agonism are capable of stimulating acute catecholamine secretion from adrenal chromaffin cells.…”

“…[1][2][3]8 In this highlighted study, Liu and colleagues 5 unexpectedly identified a new b-arrestin-1-mediated, G protein-independent, fast communication between GPCR and TRPC3, which substantially contributes to acute catecholamine secretion following AT1R activation. 5 With the specific G protein or b-arrestin-1 biased AT1R agonists and knockout mice models, Liu et al 5 found that not only the Gq-PLCb-mediated pathway but also b-arrestin-1-biased agonism are capable of stimulating acute catecholamine secretion from adrenal chromaffin cells. Surprisingly, unlike the notion that the activation of Gq-PLCb mediates secretion through IP3R sensitive intracellular Ca 2C store, the b-arrestin-1-dependent mechanism is specifically and critically dependent on the extracellular Ca 2C influx through the plasma membrane.…”

“…1,4 In addition to activating G proteins, GPCRs also transduce extracellular signals by activating arrestinmediated cell responses, such as hydrolysis of cAMP or kinase cascade signals known as the second wave of GPCR signaling (> 2-3 minutes). 5,6 However, whether arrestin also contributes to acute GPCR function remains largely unknown. TRP channels are a superfamily of Ca 2C -permeable cation nonselective channels that play critical roles in various sensory functions, such as thermosensation, mechanosensation, pain, itch, and chronic inflammatory sensation.…”