Gαq Is the Specific Mediator of PAR-1 Transactivation of Kinase Receptors in Vascular Smooth Muscle Cells.
Int J Mol Sci
; 23(22)2022 Nov 20.
Article
em En
| MEDLINE
| ID: mdl-36430902
ABSTRACT
AIMS:
G protein-coupled receptor (GPCR) transactivation of kinase receptors greatly expands the actions attributable to GPCRs. Thrombin, via its cognate GPCR, protease-activated receptor (PAR)-1, transactivates tyrosine and serine/threonine kinase receptors, specifically the epidermal growth factor receptor and transforming growth factor-ß receptor, respectively. PAR-1 transactivation-dependent signalling leads to the modification of lipid-binding proteoglycans involved in the retention of lipids and the development of atherosclerosis. The mechanisms of GPCR transactivation of kinase receptors are distinct. We aimed to investigate the role of proximal G proteins in transactivation-dependent signalling. MAINMETHODS:
Using pharmacological and molecular approaches, we studied the role of the G⺠subunits, Gâºq and Gâº11, in the context of PAR-1 transactivation-dependent signalling leading to proteoglycan modifications. KEYFINDINGS:
Pan Gâºq subunit inhibitor UBO-QIC/FR900359 inhibited PAR-1 transactivation of kinase receptors and proteoglycans modification. The Gâºq/11 inhibitor YM254890 did not affect PAR-1 transactivation pathways. Molecular approaches revealed that of the two highly homogenous Gâºq members, Gâºq and Gâº11, only the Gâºq was involved in regulating PAR-1 mediated proteoglycan modification. Although Gâºq and Gâº11 share approximately 90% homology at the protein level, we show that the two isoforms exhibit different functional roles.SIGNIFICANCE:
Our findings may be extrapolated to other GPCRs involved in vascular pathology and highlight the need for novel pharmacological tools to assess the role of G proteins in GPCR signalling to expand the preeminent position of GPCRs in human therapeutics.Palavras-chave
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Base de dados:
MEDLINE
Assunto principal:
Receptor PAR-1
/
Músculo Liso Vascular
Limite:
Humans
Idioma:
En
Ano de publicação:
2022
Tipo de documento:
Article