Endothelin-converting enzyme-1 regulates trafficking and signalling of the neurokinin 1 receptor in endosomes of myenteric neurones

Abstract/Summary

Neuropeptide signalling at the plasma membrane is terminated by neuropeptide degradation by cell-surface peptidases, and by beta-arrestin-dependent receptor desensitization and endocytosis. However, receptors continue to signal from endosomes by beta-arrestin-dependent processes, and endosomal sorting mediates recycling and resensitization of plasma membrane signalling. The mechanisms that control signalling and trafficking of receptors in endosomes are poorly defined. We report a major role for endothelin-converting enzyme-1 (ECE-1) in controlling substance P (SP) and the neurokinin 1 receptor (NK(1)R) in endosomes of myenteric neurones. ECE-1 mRNA and protein were expressed by myenteric neurones of rat and mouse intestine. SP (10 nM, 10 min) induced interaction of NK(1)R and beta-arrestin at the plasma membrane, and the SP-NK(1)R-beta-arrestin signalosome complex trafficked by a dynamin-mediated mechanism to ECE-1-containing early endosomes, where ECE-1 can degrade SP. After 120 min, NK(1)R recycled from endosomes to the plasma membrane. ECE-1 inhibitors (SM-19712, PD-069185) and the vacuolar H(+)ATPase inhibitor bafilomycin A(1), which prevent endosomal SP degradation, suppressed NK(1)R recycling by >50%. Preincubation of neurones with SP (10 nM, 5 min) desensitized Ca(2+) transients to a second SP challenge after 10 min, and SP signals resensitized after 60 min. SM-19712 inhibited NK(1)R resensitization by >90%. ECE-1 inhibitors also caused sustained SP-induced activation of extracellular signal-regulated kinases, consistent with stabilization of the SP-NK(1)R-beta-arrestin signalosome. By degrading SP and destabilizing endosomal signalosomes, ECE-1 has a dual role in controlling endocytic signalling and trafficking of the NK(1)R: promoting resensitization of G protein-mediated plasma membrane signalling, and terminating beta-arrestin-mediated endosomal signalling.

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Additional Information

Pelayo, Juan-Carlos Poole, Daniel P Steinhoff, Martin Cottrell, Graeme S Bunnett, Nigel W AR059402/AR/NIAMS NIH HHS/ DK07573/DK/NIDDK NIH HHS/ DK39957/DK/NIDDK NIH HHS/ DK43207/DK/NIDDK NIH HHS/ DK57850/DK/NIDDK NIH HHS/ FS/08/017/25027/British Heart Foundation/United Kingdom R01 AR059402/AR/NIAMS NIH HHS/ England J Physiol. 2011 Nov 1;589(Pt 21):5213-30. doi: 10.1113/jphysiol.2011.214452. Epub 2011 Aug 30.

Item Type

Article

URI

https://reading-clone.eprints-hosting.org/id/eprint/30251

Item Type

Article

Refereed

Yes

Divisions

No Reading authors. Back catalogue items

Uncontrolled Keywords

Animals Arrestins/metabolism Aspartic Acid Endopeptidases/*metabolism Calcium/metabolism Cell Membrane/metabolism Colon/metabolism Endosomes/*metabolism Female GTP-Binding Proteins/metabolism HEK293 Cells Humans Ileum/metabolism Male Metalloendopeptidases/*metabolism Mice Mice, Inbred C57BL Myenteric Plexus/*metabolism Neurons/*metabolism Rats Rats, Sprague-Dawley Receptors, Neurokinin-1/*metabolism Signal Transduction Substance P/metabolism

Date Deposited:	11 Jan 2013 14:49	Date item deposited into CentAUR
Last Modified:	23 Jun 2024 01:53	Date item last modified