Journal
CELLULAR AND MOLECULAR LIFE SCIENCES
Volume 78, Issue 23, Pages 7133-7144Publisher
SPRINGER BASEL AG
DOI: 10.1007/s00018-021-03944-1
Keywords
G-protein-coupled receptor; VGF; TLQP-21; C3aR1; C3a; gC1QR; HSPA8; Complement; Microglia; Adipocytes
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Funding
- Cure Alzheimer's Fund [DK117504, DK118150, DK102496, AG062355, AG062661]
- University of Minnesota Informatics Institute graduate assistantship program (MEN) [T32DK083250, BT-/RLF/Re-entry/38/2016]
- Department of Biotechnology, Government of India, NBRC core funds (BSS)
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The review critically evaluates the molecular identity of the TLQP-21 receptor and the proposed multi-receptor mechanism of action, confirming a critical role for C3aR1 in TLQP-21 biological activity, while data supporting a role of gC1qR and HSPA8 remain limited.
The TLQP-21 neuropeptide has been implicated in functions as diverse as lipolysis, neurodegeneration and metabolism, thus suggesting an important role in several human diseases. Three binding targets have been proposed for TLQP-21: C3aR1, gC1qR and HSPA8. The aim of this review is to critically evaluate the molecular identity of the TLQP-21 receptor and the proposed multi-receptor mechanism of action. Several studies confirm a critical role for C3aR1 in TLQP-21 biological activity and a largely conserved mode of binding, receptor activation and signaling with C3a, its first-identified endogenous ligand. Conversely, data supporting a role of gC1qR and HSPA8 in TLQP-21 activity remain limited, with no signal transduction pathways being described. Overall, C3aR1 is the only receptor for which a necessary and sufficient role in TLQP-21 activity has been confirmed thus far. This conclusion calls into question the validity of a multi-receptor mechanism of action for TLQP-21 and should inform future studies.
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