A two-receptor pathway for catabolism of Clara cell secretory protein in the kidney

Clara cell secretory protein (CCSP) is a transport protein for lipophilic substances in bronchio-alveolar fluid, plasma, and uterine secretion. It acts as a carrier for steroid hormones and polychlorinated biphenyl metabolites. Previously, the existence of receptors for uptake of CCSP-ligand complexes into the renal proximal tubules had been suggested. Using surface plasmon resonance analysis, we demonstrate that CCSP binds to cubilin, a peripheral membrane protein on the surface of proximal tubular cells. Binding to cubilin results in uptake and lysosomal degradation of CCSP in cultured cells. Surprisingly, internalization of CCSP is blocked not only by cubilin antagonists but also by antibodies directed against megalin, an endocytic receptor that does not bind CCSP but associates with cubilin. Consistent with a role of both receptors in renal uptake of CCSP in vivo, patients deficient for cubilin or mice lacking megalin exhibit a defect in tubular uptake of the protein and excrete CCSP into the urine. These findings identify a cellular pathway consisting of a CCSP-binding protein (cubilin) and an endocytic coreceptor (megalin) responsible for tissue-specific uptake of CCSP and associated ligands

Degrading traumatic memories with eye movements: a pilot functional MRI study in PTSD

Background: Eye movement desensitization and reprocessing (EMDR) is an effective treatment for posttraumatic stress disorder (PTSD). During EMDR, the patient recalls traumatic memories while making eye movements (EMs). Making EMs during recall is associated with decreased vividness and emotionality of traumatic memories, but the underlying mechanism has been unclear. Recent studies support a “working-memory” (WM) theory, which states that the two tasks (recall and EMs) compete for limited capacity of WM resources. However, prior research has mainly relied on self-report measures. Methods: Using functional magnetic resonance imaging, we tested whether “recall with EMs,” relative to a “recall-only” control condition, was associated with reduced activity of primary visual and emotional processing brain regions, associated with vividness and emotionality respectively, and increased activity of the dorsolateral prefrontal cortex (DLPFC), associated with working memory. We used a randomized, controlled, crossover experimental design in eight adult patients with a primary diagnosis of PTSD. A script-driven imagery (SDI) procedure was used to measure responsiveness to an audio-script depicting the participant's traumatic memory before and after conditions. Results: SDI activated mainly emotional processing-related brain regions (anterior insula, rostral anterior cingulate cortex (ACC), and dorsomedial prefrontal cortex), WM-related (DLPFC), and visual (association) brain regions before both conditions. Although predicted pre- to post-test decrease in amygdala activation after “recall with EMs” was not significant, SDI activated less right amygdala and rostral ACC activity after “recall with EMs” compared to post-“recall-only.” Furthermore, functional connectivity from the right amygdala to the rostral ACC was decreased after “recall with EMs” compared with after “recall-only.” Conclusions: These preliminary results in a small sample suggest that making EMs during recall, which is part of the regular EMDR treatment protocol, might reduce activity and connectivity in emotional processing-related areas. This study warrants replication in a larger sample. Highlights of the article