dc.contributor.author |
Tasma, Zoe |
|
dc.contributor.author |
Wills, Peter |
|
dc.contributor.author |
Hay, Debbie L |
|
dc.contributor.author |
Walker, Christopher S |
|
dc.coverage.spatial |
United States |
|
dc.date.accessioned |
2021-10-12T03:05:57Z |
|
dc.date.available |
2021-10-12T03:05:57Z |
|
dc.date.issued |
2020-6 |
|
dc.identifier.citation |
Pharmacology research & perspectives 8(3):e00595 Jun 2020 |
|
dc.identifier.issn |
2052-1707 |
|
dc.identifier.uri |
https://hdl.handle.net/2292/56919 |
|
dc.description.abstract |
The corticotropin-releasing factor (CRF) receptors represent potential drug targets for the treatment of anxiety, stress, and other disorders. However, it is not known if endogenous CRF receptor agonists display biased signaling, how effective CRF receptor antagonists are at blocking different agonists and signaling pathways or how receptor activity-modifying proteins (RAMPs) effect these processes. This study aimed to address this by investigating agonist and antagonist action at CRF<sub>1</sub> and CRF<sub>2</sub> receptors. We used CRF<sub>1</sub> and CRF<sub>2</sub> receptor transfected Cos7 cells to assess the ability of CRF and urocortin (UCN) peptides to activate cAMP, inositol monophosphate (IP<sub>1</sub> ), and extracellular signal-regulated kinase 1/2 signaling and determined the ability of antagonists to block agonist-stimulated cAMP and IP<sub>1</sub> accumulation. The ability of RAMPs to interact with CRF receptors was also examined. At the CRF<sub>1</sub> receptor, CRF and UCN1 activated signaling in the same manner. However, at the CRF<sub>2</sub> receptor, UCN1 and UCN2 displayed similar signaling profiles, whereas CRF and UCN3 displayed bias away from IP<sub>1</sub> accumulation over cAMP. The antagonist potency was dependent on the receptor, agonist, and signaling pathway. CRF<sub>1</sub> and CRF<sub>2</sub> receptors had no effect on RAMP1 or RAMP2 surface expression. The presence of biased agonism and agonist-dependent antagonism at the CRF receptors offers new avenues for developing drugs tailored to activate a specific signaling pathway or block a specific agonist. Our findings suggest that the already complex CRF receptor pharmacology may be underappreciated and requires further investigation. |
|
dc.format.medium |
Print |
|
dc.language |
eng |
|
dc.publisher |
Wiley |
|
dc.relation.ispartofseries |
Pharmacology research & perspectives |
|
dc.rights |
Items in ResearchSpace are protected by copyright, with all rights reserved, unless otherwise indicated. Previously published items are made available in accordance with the copyright policy of the publisher. |
|
dc.rights.uri |
https://researchspace.auckland.ac.nz/docs/uoa-docs/rights.htm |
|
dc.rights.uri |
https://creativecommons.org/licenses/by/4.0/ |
|
dc.subject |
COS Cells |
|
dc.subject |
Animals |
|
dc.subject |
Humans |
|
dc.subject |
Inositol Phosphates |
|
dc.subject |
Corticotropin-Releasing Hormone |
|
dc.subject |
Receptors, Corticotropin-Releasing Hormone |
|
dc.subject |
Cyclic AMP |
|
dc.subject |
Signal Transduction |
|
dc.subject |
Urocortins |
|
dc.subject |
HEK293 Cells |
|
dc.subject |
Receptor Activity-Modifying Protein 1 |
|
dc.subject |
Receptor Activity-Modifying Protein 2 |
|
dc.subject |
Drug Development |
|
dc.subject |
Chlorocebus aethiops |
|
dc.subject |
CRF1 |
|
dc.subject |
CRF2 |
|
dc.subject |
corticotropin releasing factor |
|
dc.subject |
functional selectivity |
|
dc.subject |
intracellular signaling |
|
dc.subject |
probe-dependent antagonism |
|
dc.subject |
Animals |
|
dc.subject |
COS Cells |
|
dc.subject |
Chlorocebus aethiops |
|
dc.subject |
Corticotropin-Releasing Hormone |
|
dc.subject |
Cyclic AMP |
|
dc.subject |
Drug Development |
|
dc.subject |
HEK293 Cells |
|
dc.subject |
Humans |
|
dc.subject |
Inositol Phosphates |
|
dc.subject |
Receptor Activity-Modifying Protein 1 |
|
dc.subject |
Receptor Activity-Modifying Protein 2 |
|
dc.subject |
Receptors, Corticotropin-Releasing Hormone |
|
dc.subject |
Signal Transduction |
|
dc.subject |
Urocortins |
|
dc.subject |
Science & Technology |
|
dc.subject |
Life Sciences & Biomedicine |
|
dc.subject |
Pharmacology & Pharmacy |
|
dc.subject |
corticotropin releasing factor |
|
dc.subject |
CRF1 |
|
dc.subject |
CRF2 |
|
dc.subject |
functional selectivity |
|
dc.subject |
intracellular signaling |
|
dc.subject |
probe-dependent antagonism |
|
dc.subject |
ACTIVITY-MODIFYING PROTEINS |
|
dc.subject |
GENE-RELATED PEPTIDE |
|
dc.subject |
CALCITONIN RECEPTOR |
|
dc.subject |
CONCISE GUIDE |
|
dc.subject |
SIGNAL-TRANSDUCTION |
|
dc.subject |
CRF1 RECEPTORS |
|
dc.subject |
FACTOR TYPE-1 |
|
dc.subject |
HORMONE CRH |
|
dc.subject |
PHARMACOLOGY |
|
dc.subject |
UROCORTINS |
|
dc.subject |
1115 Pharmacology and Pharmaceutical Sciences |
|
dc.subject |
Biomedical |
|
dc.subject |
Basic Science |
|
dc.subject |
Mental Health |
|
dc.subject |
5.1 Pharmaceuticals |
|
dc.subject |
0304 Medicinal and Biomolecular Chemistry |
|
dc.subject |
1115 Pharmacology and Pharmaceutical Sciences |
|
dc.title |
Agonist bias and agonist-dependent antagonism at corticotrophin releasing factor receptors. |
|
dc.type |
Journal Article |
|
dc.identifier.doi |
10.1002/prp2.595 |
|
pubs.issue |
3 |
|
pubs.begin-page |
e00595 |
|
pubs.volume |
8 |
|
dc.date.updated |
2021-09-22T02:25:02Z |
|
dc.rights.holder |
Copyright: The author |
en |
pubs.author-url |
https://www.ncbi.nlm.nih.gov/pubmed/32529807 |
|
pubs.publication-status |
Published |
|
dc.rights.accessrights |
http://purl.org/eprint/accessRights/OpenAccess |
en |
pubs.subtype |
Research Support, Non-U.S. Gov't |
|
pubs.subtype |
research-article |
|
pubs.subtype |
Journal Article |
|
pubs.elements-id |
804594 |
|
dc.identifier.eissn |
2052-1707 |
|
pubs.number |
ARTN e00595 |
|
pubs.online-publication-date |
2020-6-11 |
|