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Published VersionCC BY V4.0, Open Access
Journal article
G alpha q Is the Specific Mediator of PAR-1 Transactivation of Kinase Receptors in Vascular Smooth Muscle Cells
International Journal of Molecular Sciences, Vol.23(22), pp.1-13
2022
PMID: 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-beta 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. Main Methods: Using pharmacological and molecular approaches, we studied the role of the G alpha subunits, G alpha q and G alpha 11, in the context of PAR-1 transactivation-dependent signalling leading to proteoglycan modifications. Key Findings: Pan G alpha q subunit inhibitor UBO-QIC/FR900359 inhibited PAR-1 transactivation of kinase receptors and proteoglycans modification. The G alpha q/11 inhibitor YM254890 did not affect PAR-1 transactivation pathways. Molecular approaches revealed that of the two highly homogenous G alpha q members, G alpha q and G alpha 11, only the G alpha q was involved in regulating PAR-1 mediated proteoglycan modification. Although G alpha q and G alpha 11 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.
Details
- Title
- G alpha q Is the Specific Mediator of PAR-1 Transactivation of Kinase Receptors in Vascular Smooth Muscle Cells
- Authors
- Danielle Kamato (Corresponding Author) - Griffith UniversityMai Gabr (Author) - The University of QueenslandHirushi Kumarapperuma (Author) - Griffith UniversityZheng J. Chia (Author) - Griffith UniversityWenhua Zheng (Author) - University of MacauSuowen Xu (Author) - University of Science and Technology of ChinaNarin Osman (Author) - RMIT UniversityPeter J. Little (Author) - University of the Sunshine Coast, Queensland, School of Health and Behavioural Sciences - Legacy
- Publication details
- International Journal of Molecular Sciences, Vol.23(22), pp.1-13
- Publisher
- MDPI AG
- Date published
- 2022
- DOI
- 10.3390/ijms232214425
- ISSN
- 1422-0067; 1661-6596
- PMID
- 36430902
- Copyright note
- © 2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
- Grant note
- 1160925 / NHMRC-Peter Doherty; National Health and Medical Research Council (NHMRC) of Australia University of Queensland 102129 / National Heart Foundation of Australia
- Organisation Unit
- School of Health; School of Health and Behavioural Sciences - Legacy
- Language
- English
- Record Identifier
- 99696657202621
- Output Type
- Journal article
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