Monitoring paxillin in astrocytes reveals the significance of the adhesion GPCR VLGR1/ADGRV1 for focal adhesion assembly

by Selleckchem | Apr 04 2023

VLGR1/ADGRV1 (very large G protein-coupled receptor-1) is the largest adhesion G protein-coupled receptor aGPCRs. Mutations in VLGR1/ADGRV1 are associated with human Usher syndrome, the most common form of deaf-blindness, and also with epilepsy in humans and mice. VLGR1 is expressed almost ubiquitously, but is mainly found in the CNS and in the sensory cells of the eye and inner ear. Little is known about the pathogenesis of the diseases related to VLGR1. We previously identified VLGR1 as a vital component of focal adhesions (FA) serving as a metabotropic mechanoreceptor controls cell spreading and migration. FAs are highly dynamic and turnover in response to internal and external signals. Here, we aimed to elucidate how VLGR1 participates in FA turnover. Nocodazole washouts and live cell imaging of paxillin-DsRed2 consistently showed that FA disassembly was not altered, .but de novo assembly of FA was significantly delayed in Vlgr1-deficient astrocytes, indicating that VLGR1 is enrolled in FA assembly. In FRAP experiments recovery rates were significantly reduced in Vlgr1-deficient FAs, indicating reduced turnover kinetics in VLGR1-deficient FAs. We showed that VLGR1 regulates cell migration by controlling the FA turnover during their assembly and expect novel insights into pathomechanisms related to pathogenic dysfunctions of VLGR1.

Comments：

VLGR1/ADGRV1 is a very large adhesion G protein-coupled receptor, which is expressed almost ubiquitously, but mainly found in the CNS and in the sensory cells of the eye and inner ear. Mutations in VLGR1/ADGRV1 have been associated with human Usher syndrome, the most common form of deaf-blindness, and epilepsy in humans and mice. However, little is known about the pathogenesis of the diseases related to VLGR1.

Previous research has identified VLGR1 as a vital component of focal adhesions (FA), which are structures that link the cell to the extracellular matrix and serve as a platform for signaling and force transmission. FAs are highly dynamic and turnover in response to internal and external signals. The researchers aimed to elucidate how VLGR1 participates in FA turnover.

The researchers used nocodazole washouts and live cell imaging of paxillin-DsRed2 to investigate the role of VLGR1 in FA assembly and disassembly. They found that FA disassembly was not altered in Vlgr1-deficient astrocytes, but de novo assembly of FA was significantly delayed, indicating that VLGR1 is involved in FA assembly. They also found that the turnover kinetics of VLGR1-deficient FAs were reduced, indicating that VLGR1 regulates FA turnover during their assembly.

Furthermore, the researchers showed that VLGR1 regulates cell migration by controlling FA turnover during their assembly. These findings provide novel insights into the pathomechanisms related to pathogenic dysfunctions of VLGR1.

In summary, VLGR1 plays an important role in FA turnover during their assembly and regulates cell migration. The dysfunctions of VLGR1 may contribute to the pathogenesis of Usher syndrome, epilepsy, and other related diseases.