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Multiple Players Vying for One Target: Regulation of Differential Signaling Fate of Corticotropin‐releasing Factor Receptor 1 (CRF 1 )
Author(s) -
Mahajan Shilpi,
Hasdemir Burcu,
Liao Min,
Bhargava Aditi
Publication year - 2012
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.26.1_supplement.1158.2
Subject(s) - sensitization , medicine , receptor , endocrinology , chemistry , corticotropin releasing hormone , urocortin , biology , neuroscience
Activation of CRF 1 by CRF, urocortin (Ucn1) or both, is critical in stress‐related pathophysiological conditions like anxiety, depression, and irritable bowel syndrome. We sought to determine how CRF 1 activation by multiple ligands evokes distinct cellular responses. Mass spectrometry and HPLC showed endothelin‐converting enzyme‐1 (ECE‐1) differentially degrades CRF and Ucn1; ECE‐1 cleaves Ucn1, but not CRF, at critical residue Arginine‐34/35’, which is essential for ligand‐receptor binding. ECE‐1 cleavage disrupts the Ucn1‐CRF 1 complex to alter Ucn1‐, but not CRF‐mediated Ca 2+ mobilization. ECE‐1 inhibition disrupted Ucn1‐, but not CRF‐induced CRF 1 recycling and re‐sensitization, but did not prolong the association of CRF 1 with β‐arrestins (βARRs). Ucn1‐, but not CRF‐induced CRF 1 recycling was dependent on Rab11 activity and re‐sensitization was dependent on both Rab4 and Rab11 activity. CRF 1 behaves like a class A GPCR with respect to transient βARR interaction, but like a class B GPCR with respect to slow recycling. We propose a novel mechanism by which two ligands acting on the same receptor can result in distinct re‐sensitization and downstream signaling– differential degradation by ECE‐1. NIH DK080787 and Hellman Family Foundation grant to AB.