Disease-associated mutations offer new clues to protein function (14 Sept 2018)
NMDA receptors are transmembrane proteins that help regulate our memories and behavior. Random changes in the genes encoding NMDA receptor subunits, yielding de novo missense mutations, are associated with epilepsy, autism spectrum disorder, intellectual disability, and schizophrenia. The most prevalent site at which missense mutations occur in NMDA receptors is at a conserved glycine in the transmembrane region forming the ion channel. In a recent paper published in Nature Communications, Lonnie Wollmuth's group has shown that this glycine works in an unanticipated way: it acts as a pivot point or hinge which allows for expansion of the inner part of the ion channel enhancing NMDA receptor signaling. Disease-associated mutations prevent this movement and, hence, normal NMDA receptor signaling. These insights suggest new strategies for targeting NMDA receptors in the treatment of neurological disorders.
Expansion of the inner pore permitted mainly by the GluN1 M4 conserved glycine facilitates NMDA receptor gating and Ca2+ permeation.
Measures of traumatic stress exposure based on changes in gene regulatory function (23 Aug 2018)
Surprisingly, given the well established deleterious effects of traumatic stress exposure, there is no simple, or even complex, way to objectively measure the level of traumatic stress to which an individual has been exposed. A molecular diagnostic tool that could robustly measure levels of traumatic stress exposure would be of considerable value in assessing the risk of developing post-traumatic stress disorder or stress-induced depression after exposure to stressful events. In a recent paper published in Translational Psychiatry, Drs. McKinnon and Rosati's group has shown that the gene regulatory network encodes sufficient information to reliably distinguish unstressed individuals from those who have been exposed to traumatic stress. These results suggest that it is possible to create diagnostic measures of stress exposure using molecular markers from the gene regulatory network.