Trends in Pharmacological Sciences
ReviewSex-specific cell signaling: the corticotropin-releasing factor receptor model
Section snippets
Biased signaling at seven-transmembrane receptors
Understanding of how seven-transmembrane receptor (7-TMR) function has undergone an evolution over the past decade and transformed approaches to drug development. Rather than the simple model in which ligand binding initiates a cascade of reactions that is determined by receptor coupling to specific guanine nucleotide binding proteins (G proteins), it is now recognized that 7-TMRs can associate with multiple G proteins. Moreover, evidence for the association of 7-TMRs with β-arrestin adaptor
CRF, stress, and disease
Sex differences in disease prevalence are reported for many diseases but are particularly apparent for stress-related psychiatric and medical diseases, including anxiety, depression, post-traumatic stress disorder (PTSD), irritable bowel syndrome (IBS), inflammatory disorders, and metabolic syndrome, many of which are nearly two times more prevalent in females (http://www.hcp.med.harvard.edu/ncs/ftpdir/NCS-R_Lifetime_Prevalence_Estimates.pdf) 10, 11. Certain disorders that have been associated
CRF1 signaling
CRF exerts its effects through two receptor subtypes, CRF1 and CRF2. Genes for CRF1 and CRF2 have been cloned 22, 23 and their distinct distribution, pharmacological specificity, signaling, and trafficking have been described (for a review, see [16]. This review focuses on CRF1, the receptor subtype that is the most prominent in the brain and that is thought to mediate most aspects of the stress response including ACTH release, arousal, and anxiogenic effects. Notably, the evidence for sex
Sex differences in CRF1 neuronal responses
A target of CRF neurotransmission in the brain is the pontine nucleus LC [38], which is the major source of norepinephrine in the brain. CRF containing axon terminals synapse with LC dendrites, and CRF microinfused directly onto LC neurons in vivo or in vitro increases discharge activity of the cells by inhibiting potassium currents 39, 40, 41. CRF-induced activation of the LC–norepinephrine system during stress is thought to be important for initiating arousal and promoting cognitive
Sex differences in CRF1–Gs-dependent signaling
CRF activation of LC neurons is differentially attenuated by the PKA antagonist, Rp-cAMP-S, which almost completely blocks the effect in females, while producing only a partial attenuation in male rats, consistent with differential CRF1 signaling [8]. Confirmatory evidence for sex differences in CRF1 signaling was derived from immunoprecipitation of CRF1 from the rat cortex, a tissue of high CRF1 expression and lacking CRF2 [44]. Immunoprecipitated CRF1 from the female rat cortex
Sex differences in CRF1 receptor trafficking
The initial descriptions of stress-induced CRF1 internalization in vivo were based on studies of LC neurons from male rats and are consistent with the observation of a decreased maximum response in the CRF dose–response curve for LC activation observed at the same time following stress [36]. In contrast to males, swim stress does not promote CRF1 internalization in LC neurons of female rats or decrease the CRF maximal response [8]. The cellular localization of CRF1 is remarkably opposite in
Consequences of sex differences in CRF1 signaling in conditions of CRF overexpression
Increased CRF1–Gs coupling together with decreased CRF1 internalization would render female neurons more sensitive to CRF and less able to adapt to excessive CRF (Figure 2). This is clinically relevant because excessive CRF has been implicated in many stress-related disorders that are more prevalent in females 18, 19, 20. The pathological condition of excessive CRF has been modeled using CRF overexpressing mice (CRF-OE) 45, 46. A well-characterized CRF-OE model is a transgenic line in which CRF
Sex biased CRF signaling
In addition to enabling receptor internalization, it is now well recognized that β-arrestin 2 can engage G protein-independent signaling cascades by scaffolding receptors to signaling molecules [1]. Given this function, the implications of sex differences in CRF1–β-arrestin association are much broader than can be attributed to differences in CRF1 internalization alone. β-Arrestin 2 signaling includes MAPK (e.g., ERK2, JNK3, and p38), tyrosine kinases (e.g., c-SRC), AKT, PI3 kinase, and RhoA
Sex biased signaling of other receptors
Given the shared characteristics of different GPCRs, sex biased signaling would be predicted to be a property of other GPCRs. Although this has not yet been systematically studied for receptors other than CRF1, evidence for differential signaling in males and females exists for several GPCRs and in some cases there is evidence for differential coupling of GPCRs to G proteins, as has been demonstrated for CRF1. For example, sex differences in βAR–Gs coupling have been demonstrated in rat
Clinical and therapeutic implications of sex biased receptor signaling
Sex biased receptor coupling and signaling has important ramifications for understanding disease and developing therapeutics. Focusing on the CRF system alone, it implies that the cellular reactions initiated by stressors will differ to some extent in males and females and this could account for a different expression of stress-related pathology. Given the many and diverse diseases that have been linked to stress, elucidating how differences in CRF1 signal transduction translate to different
Concluding remarks
This review integrates convergent findings supporting the novel concept of sex differences in receptor signaling and trafficking, using CRF1 as a model. Sex differences in Gs coupling would confer differences in agonist sensitivity and in the case of CRF, differences in acute responses to stressors. Differences in receptor association with β-arrestin influence receptor trafficking and the ability to adapt to the excessive CRF that is predicted to be present in diseases related to severe or
Acknowledgements
The authors wish to acknowledge Mr. Paul Palcko for artwork. Supported by PHS grants MH092438 and 040008.
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