Fig. 9.

ECE-1 activity determines differential recycling fate of CRF₁ upon Ucn1- or CRF-stimulation depending on agonist dose. 1, CRF or Ucn1 binds and activates CRF₁. 2, βARR transiently associate with the receptor to mediate desensitization. 3, CRF₁ is endocytosed to Rab5 containing early endosomes. 4, Under low agonist conditions, ECE-1 facilitates dissociation of the ligands from CRF₁, allowing CRF₁ to recycle and resensitize. 5, Under high agonist conditions, ECE-1 facilitates removal of Ucn1 from CRF₁, thereby causing Ucn1-mediated receptor to recycle and resensitize. CRF then dissociates from CRF₁ by an ECE-1 independent mechanism (presumably by an unknown peptidase?) that allows the freed receptor to recycle and resensitize. 6, Rab11 knockdown studies suggest that CRF₁ recycles and resensitizes via a Rab11-dependent pathway. The question mark (?) indicates that we did not test this at a low agonist concentration. 7, Recycled CRF₁ is available for resensitization by CRF or Ucn1. 8, ECE-1 is also present at the plasma membrane and gets constitutively shuttled between the plasma membrane and endosomes. 9, At low/basal agonist concentrations, ECE-1 activity regulates both Ucn1- and CRF-mediated Ca²⁺ signaling, whereas ECE-1 does not appear to affect Gαs-coupled CRF₁ and downstream cAMP signaling. 10, At high/pathophysiological agonist concentrations, ECE-1 activity regulates Ucn1-, but not CRF-mediated Ca²⁺ signaling, whereas ECE-1 does not appear to affect CRF₁-mediated cAMP signaling. memb., Membrane.