Biased signaling through G‐protein‐coupled PROKR2 receptors harboring missense mutations. Issue 8 (15th May 2014)
- Record Type:
- Journal Article
- Title:
- Biased signaling through G‐protein‐coupled PROKR2 receptors harboring missense mutations. Issue 8 (15th May 2014)
- Main Title:
- Biased signaling through G‐protein‐coupled PROKR2 receptors harboring missense mutations
- Authors:
- Sbai, Oualid
Monnier, Carine
Dodé, Catherine
Pin, Jean‐Philippe
Hardelin, Jean‐Pierre
Rondard, Philippe - Abstract:
- Abstract : Various missense mutations in the gene coding for prokineticin receptor 2 (PROKR2), a G‐protein‐coupled receptor, have been identified in patients with Kallmann syndrome. However, the functional consequences of these mutations on the different signaling pathways of this receptor have not been studied. We first showed that the wild‐type PROKR2 can activate different G‐protein subtypes (Gq, Gs, and Gi/o ) and recruit β‐arrestins in transfected HEK‐293 cells. We then examined, for each of these signaling pathways, the effects of 9 mutations that did not significantly impair cell surface targeting or ligand binding of the receptor. Four mutant receptors showing defective Gq signaling (R85C, R85H, R164Q, and V331M) could still recruit β‐arrestins on ligand activation, which may cause biased signaling in vivo. Conversely, the R80C receptor could activate the 3 types of G proteins but could not recruit β‐arrestins. Finally, the R268C receptor could recruit β‐arrestins and activate the Gq and Gs signaling pathways but could not activate the Gi/o signaling pathway. Our results validate the concept that mutations in the genes encoding membrane receptors can bias downstream signaling in various ways, possibly leading to pathogenic and, perhaps in some cases, protective (e.g., R268C) effects.—Sbai, O., Monnier, C., Dodé, C., Pin, J.‐P., Hardelin, J.‐P., Rondard, P. Biased signaling through G‐protein‐coupled PROKR2 receptors harboring missense mutations. FASEB J. 28, 3734–3744Abstract : Various missense mutations in the gene coding for prokineticin receptor 2 (PROKR2), a G‐protein‐coupled receptor, have been identified in patients with Kallmann syndrome. However, the functional consequences of these mutations on the different signaling pathways of this receptor have not been studied. We first showed that the wild‐type PROKR2 can activate different G‐protein subtypes (Gq, Gs, and Gi/o ) and recruit β‐arrestins in transfected HEK‐293 cells. We then examined, for each of these signaling pathways, the effects of 9 mutations that did not significantly impair cell surface targeting or ligand binding of the receptor. Four mutant receptors showing defective Gq signaling (R85C, R85H, R164Q, and V331M) could still recruit β‐arrestins on ligand activation, which may cause biased signaling in vivo. Conversely, the R80C receptor could activate the 3 types of G proteins but could not recruit β‐arrestins. Finally, the R268C receptor could recruit β‐arrestins and activate the Gq and Gs signaling pathways but could not activate the Gi/o signaling pathway. Our results validate the concept that mutations in the genes encoding membrane receptors can bias downstream signaling in various ways, possibly leading to pathogenic and, perhaps in some cases, protective (e.g., R268C) effects.—Sbai, O., Monnier, C., Dodé, C., Pin, J.‐P., Hardelin, J.‐P., Rondard, P. Biased signaling through G‐protein‐coupled PROKR2 receptors harboring missense mutations. FASEB J. 28, 3734–3744 (2014). www.fasebj.org … (more)
- Is Part Of:
- FASEB journal. Volume 28:Issue 8(2014)
- Journal:
- FASEB journal
- Issue:
- Volume 28:Issue 8(2014)
- Issue Display:
- Volume 28, Issue 8 (2014)
- Year:
- 2014
- Volume:
- 28
- Issue:
- 8
- Issue Sort Value:
- 2014-0028-0008-0000
- Page Start:
- 3734
- Page End:
- 3744
- Publication Date:
- 2014-05-15
- Subjects:
- Kallmann syndrome -- β‐arrestin -- prokineticin
Biology -- Periodicals
Biology, Experimental -- Periodicals
570 - Journal URLs:
- http://onlinelibrary.wiley.com/ ↗
- DOI:
- 10.1096/fj.13-243402 ↗
- Languages:
- English
- ISSNs:
- 0892-6638
- Deposit Type:
- Legaldeposit
- View Content:
- Available online (eLD content is only available in our Reading Rooms) ↗
- Physical Locations:
- British Library DSC - BLDSS-3PM
British Library HMNTS - ELD Digital store - Ingest File:
- 13312.xml