The molecular identity of the TLQP-21 peptide receptor

Abstract

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.

TLQP-21 is a low potency partial C3aR activator on human primary macrophages

“…TLQP-21 is a neuropeptide with important endocrine and enteroendocrine functions demonstrated by multiple groups ( 2 , 3 ). Several studies have reported the complement receptor C3aR as an endogenous receptor for TLQP-21 ( 3 , 7 , 8 , 13 , 16 ).…”

“…Among them, TLQP-21 is a 21-residue peptide derived from the C-terminus (residues 556-576) of the VGF precursor protein (3). Using the expression of VGF mRNA as a proxy, past studies have suggested the expression of TLQP-21 in the central and peripheral nervous system and in several neuroendocrine glands including the pancreas, adrenal medullar and pituitary, however, further investigation using more specific molecular tools are needed to confirm these findings (2)(3)(4). TLQP-21 possesses pleiotropic roles in physiology and cell biology, including reducing obesity by decreasing food intake and/or increasing energy expenditure; potentiating adrenergic-induced lipolysis in adipocytes; modulating gastric contractility and acid secretion; reproduction; nociception; neuroprotection and modulation of microglia functions (2,3).…”

“…In recent years, three possible binding targets of TLQP-21 have been identified: the globular C1q receptor (5,6), heat shock cognate 71 kDa protein A8 (HSPA8) and the complement C3a receptor (C3aR) (1,7), with C3aR being the most extensively studied (2,8). C3aR is a classical G protein-coupled receptor which is the cognate receptor for the complement peptide C3a (9).…”

“…VGF (non-acronym) is a large neuropeptide precursor (~68 kDa) classified as a member of the extended granin protein family ( 1 ). VGF is cleaved by the prohormone convertases such as prohormone convertase (PC) 1/3 and PC2 to generate a variety of bioactive peptides of low molecular weights ( 2 ). Among them, TLQP-21 is a 21-residue peptide derived from the C -terminus (residues 556-576) of the VGF precursor protein ( 3 ).…”

“…Therefore, in the present study, we aimed to define the pharmacological activity of TLQP-21 on the cell signalling of human and murine primary macrophages. Human TLQP-21 (hTLQP-21) and mouse TLQP-21 (mTLQP-21) harbour 24% (5 out of 21) difference in their amino acid sequences ( 2 , 7 ). Considering the differential activities of the two molecules as reported previously ( 16 , 17 ), both hTLQP-21 and mTLQP-21 were synthesised, and comparatively analysed.…”