Mechanisms of initiation and termination of signalling by neuropeptide receptors: a comparison with the proteinase-activated receptors.
Biological responses to neuropeptides are rapidly attenuated by overlapping mechanisms that include peptide degradation by cell-surface proteases, receptor uncoupling from heterotrimeric G-proteins and receptor endocytosis. We have investigated the mechanisms that terminate the proinflammatory effects of the neuropeptide substance P (SP), which are mediated by the neurokinin 1 receptor (NK1R). Neutral endopeptidase degrades SP in the extracellular fluid and is one of the first mechanisms to terminate signalling. G-protein receptor kinases and second-messenger kinases phosphorylate the NK1R to permit interaction with beta-arrestins, which uncouple the receptor from G-proteins to terminate the signal. SP-induces NK1R endocytosis by a beta-arrestin-dependent mechanism, which also involves the GTPases dynamin and Rab5a. Endocytosis contributes to desensitization by depleting receptors from the cell surface. Disruption of these mechanisms results in uncontrolled stimulation and disease. Thus the deletion of neutral endopeptidase in mice exacerbates inflammation of many tissues. There are similarities and distinct differences in the mechanisms that regulate signalling by neuropeptide receptors and other G-protein-coupled receptors, in particular those that are activated irreversibly by proteolysis.
Defea
K
K
Department of Surgery, University of California San Francisco, 521 Parnassus Avenue, San Francisco, CA 94143-0660, USA.
Schmidlin
F
F
Déry
O
O
Grady
E F
EF
Bunnett
N W
NW
D000818:Animals; D019390:Arrestins / Q000378:metabolism; D002462:Cell Membrane / Q000378:metabolism; D034281:Dynamins; D004705:Endocytosis; D010450:Endopeptidases / Q000378:metabolism*; D020558:GTP Phosphohydrolases / Q000378:metabolism; D006801:Humans; D008407:Mast Cells / Q000378:metabolism; D051379:Mice; D008954:Models, Biological; D015260:Neprilysin / Q000378:metabolism; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D044464:Receptor, PAR-2; D018040:Receptors, Neurokinin-1 / Q000378:metabolism; D018013:Receptors, Neuropeptide / Q000378:metabolism*; D018179:Receptors, Thrombin / Q000378:metabolism; D012697:Serine Endopeptidases / Q000378:metabolism; D015398:Signal Transduction; D013373:Substance P / Q000378:metabolism*; D013997:Time Factors; D053802:Tryptases; D000071557:beta-Arrestins; D020696:rab5 GTP-Binding Proteins / Q000378:metabolism
D019390:Arrestins; D044464:Receptor, PAR-2; D018040:Receptors, Neurokinin-1; D018013:Receptors, Neuropeptide; D018179:Receptors, Thrombin; C509190:Tpsb2 protein, mouse; D000071557:beta-Arrestins; D013373:Substance P; D017346:Protein Serine-Threonine Kinases; D010450:Endopeptidases; D012697:Serine Endopeptidases; C509222:Tpsab1 protein, mouse; D053802:Tryptases; D015260:Neprilysin; D020558:GTP Phosphohydrolases; D020696:rab5 GTP-Binding Proteins; D034281:Dynamins