Adrenocorticotropic Hormone (ACTH) Responses Require Actions of the Melanocortin-2 Receptor Accessory Protein on the Extracellular Surface of the Plasma Membrane.

The melanocortin-2 (MC2) receptor is a G protein-coupled receptor that mediates responses to ACTH. The MC2 receptor acts in concert with the MC2 receptor accessory protein (MRAP) that is absolutely required for ACTH binding and signaling. MRAP has a single transmembrane domain and forms a highly unusual antiparallel homodimer that is stably associated with MC2 receptors at the plasma membrane. Despite the physiological importance of the interaction between the MC2 receptor and MRAP, there is little understanding of how the accessory protein works. The dual topology of MRAP has made it impossible to determine whether highly conserved and necessary regions of MRAP are required on the intracellular or extracellular face of the plasma membrane. The strategy used here was to fix the orientation of two antiparallel MRAP molecules and then introduce inactivating mutations on one side of the membrane or the other. This was achieved by engineering proteins containing tandem copies of MRAP fused to the amino terminus of the MC2 receptor. The data firmly establish that only the extracellular amino terminus (Nout) copy of MRAP, oriented with critical segments on the extracellular side of the membrane, is essential. The transmembrane domain of MRAP is also required in only the Nout orientation. Finally, activity of MRAP-MRAP-MC2-receptor fusion proteins with inactivating mutations in either MRAP or the receptor was rescued by co-expression of free wild-type MRAP or free wild-type receptor. These results show that the basic MRAP-MRAP-receptor signaling unit forms higher order complexes and that these multimers signal.

Systematic review of depression and suicidality in child and adolescent (CAP) refugees.

Child adversity and trauma has been shown to have incredible detrimental effects physically and mentally in the subsequent adult life. Importantly, refugee minors are especially vulnerable to trauma. Thus far there are numerous studies examining cohorts of child and adolescent refugees and their impact on mental health in general and post-traumatic stress disorder (PTSD), but none have focused specifically on depression and suicide.  The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were followed for the current systematic review. 25 articles out of 2660 queried were identified to be included in the review. Overall, CAP refugees have increased risk for major depressive disorder and suicidality compared to the general population to which they have immigrated, regardless of origin. Due to the differences in the assessment tools used, it is hard to parse out if mood disturbance was secondary to major depressive disorder (MDD) or PTSD, or that suicidality is independent or a sequela of MDD/PTSD. Given the vulnerability of CAP refugees after trauma future studies are needed to further elucidate their risk of concurrent depression and suicidality, so as to facilitate appropriate treatment.