Roles of proteolysis in regulation of GPCR function

Abstract

The enzymatic activity of peptidases must be tightly regulated to prevent uncontrolled hydrolysis of peptide bonds, which could have devastating effects on biological systems. Peptidases are often generated as inactive propeptidases, secreted with endogenous inhibitors, or they are compartmentalized. Propeptidases become active after proteolytic removal of N‐terminal activation peptides by other peptidases. Some peptidases only become active towards substrates only at certain pHs, thus confining activity to specific compartments or conditions. This review discusses the different roles proteolysis plays in regulating GPCRs. At the cell‐surface, certain GPCRs are regulated by the hydrolytic inactivation of bioactive peptides by membrane‐anchored peptidases, which prevent signalling. Conversely, cell‐surface peptidases can also generate bioactive peptides, which directly activate GPCRs. Alternatively, cell‐surface peptidases activated by GPCRs, can generate bioactive peptides to cause transactivation of receptor tyrosine kinases, thereby promoting signalling. Certain peptidases can signal directly to cells, by cleaving GPCR to initiate intracellular signalling cascades. Intracellular peptidases also regulate GPCRs; lysosomal peptidases destroy GPCRs in lysosomes to permanently terminate signalling and mediate down‐regulation; endosomal peptidases cleave internalized peptide agonists to regulate GPCR recycling, resensitization and signalling; and soluble intracellular peptidases also participate in GPCR function by regulating the ubiquitination state of GPCRs, thereby altering GPCR signalling and fate. Although the use of peptidase inhibitors has already brought success in the treatment of diseases such as hypertension, the discovery of new regulatory mechanisms involving proteolysis that control GPCRs may provide additional targets to modulate dysregulated GPCR signalling in disease.

The N-terminus of GPR37L1 is proteolytically processed by matrix metalloproteases

“…Like the results with BB94 (Figure 2c), the presence of TAPI-1 or TAPI-2 prevented GPR37L1-eYFP cleavage in a concentration-dependent manner (Figure 2e & 2f). From these data, we conclude that one or more ADAM family members that are not inhibited by TIMPs but have a Zn 2+ catalytic domain, that is ADAMs 8,9,15,19,20,21,and 30 (35), may be responsible for GPR37L1 N-terminal proteolysis.…”

“…Currently, the molecular pharmacology of GPR37L1 is poorly understood (15), although the neurotrophic factor prosaposin [and its synthetic peptide derivative prosaptide (TX14A)] have been proposed as endogenous GPR37L1 and GPR37 ligands (16). Intriguingly, analyses of normal human cerebrospinal fluid (CSF) identified peptides (17)(18)(19) that are identical to three distinct regions of the GPR37L1 N-terminus, suggesting that perhaps GPR37L1 is processed and activated by a mechanism akin to that of the protease-activated receptors (PARs) (20). In this study (See Footnote) , we tested the hypothesis that the N-terminus of GPR37L1 is post-translationally modified and that this may influence receptor function.…”

Mechanism of Neutrophil Dysfunction: Neutrophil Serine Proteases Cleave and Inactivate the C5a Receptor

“…However, C5a-induced NSP secretion can inactivate the C5aR on neighboring cells that have not been in contact with C5a. Internalization of the GPCRs followed by endosomal degradation and/or recycling to the cell surface is well documented and a very quick process that happens within minutes (38). Several studies investigated the fate of C5aR after ligand binding.…”

Elastase-2 knockout mice display anxiogenic‐ and antidepressant-like phenotype: putative role for BDNF metabolism in prefrontal cortex

“…Beyond the changes in BDNF levels, the behavioral phenotype of ELA2KO can be interpreted bas ed on the role of elastases on protease-activated receptors (PAR), mainly PAR-2 43 . The function of several G-protein-coupled receptors can be regulated by proteases have been described 44 .…”