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 CRF1 and CRF2 receptors. We used CRF1 and CRF2 receptor transfected Cos7 cells to assess the ability of CRF and urocortin (UCN) peptides to activate cAMP, inositol monophosphate (IP1), and extracellular signal‐regulated kinase 1/2 signaling and determined the ability of antagonists to block agonist‐stimulated cAMP and IP1 accumulation. The ability of RAMPs to interact with CRF receptors was also examined. At the CRF1 receptor, CRF and UCN1 activated signaling in the same manner. However, at the CRF2 receptor, UCN1 and UCN2 displayed similar signaling profiles, whereas CRF and UCN3 displayed bias away from IP1 accumulation over cAMP. The antagonist potency was dependent on the receptor, agonist, and signaling pathway. CRF1 and CRF2 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.
Highlights
The neuropeptide, corticotropin releasing factor (CRF) is a member of the secretin peptide family.[1,2] CRF is expressed throughout the central nervous system and in peripheral tissues.[3]
No specific CRF receptor targeted therapy has been approved by regulatory authorities, several small molecule antagonists have been developed and there is considerable data around the safety and pharmacokinetics of these molecules.[18,42]
In order to achieve this, we first need a better understanding of how the CRF receptors signal and how effectively CRF receptor antagonists block signaling
Summary
The neuropeptide, corticotropin releasing factor (CRF) is a member of the secretin peptide family.[1,2] CRF is expressed throughout the central nervous system and in peripheral tissues.[3]. The CRF1 receptor binds CRF and UCN1 with high affinity, whereas the CRF2 receptor can bind CRF, UCN1, UCN2, and UCN3 with high affinity.[16,17] The CRF receptors have already been exploited in drug discovery resulting in small molecule CRF1 antagonists which have been explored in clinical trials to treat anxiety, depression and addiction.[18] Several CRF1 receptor antagonists are reportedly safe and clinical trials are ongoing, whereas other CRF receptor antagonists have been discontinued due to a lack of efficacy.[18] The underlying basis for these differences is not well understood but it is possible that CRF receptor pharmacology is more complicated than presently appreciated Both the CRF1 and CRF2 receptors have functional splice variants and have been reported to form heterodimers with a receptor activity-modifying protein (RAMP).[19,20,21] there are conflicting reports for RAMP interactions.[22] RAMPs can form heterodimers with several GPCRs altering cell surface expression, receptor trafficking, pharmacology, and/or signaling properties.[23]. We investigated how effectively CRF receptor antagonists block CRF- or UCN1-stimulated receptor signaling
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