Capturing transporters in motion
When a neurotransmitter’s job is done, the chemicals are removed from the synapse via membrane proteins called “transporters.” One family of transporters – the neurotransmitter:sodium symporter (NSS) – uses energy derived from the natural sodium gradient to fuel the transport of neurotransmitters like serotonin, norepinephrine and dopamine (chemicals involved in mood regulation and addiction).
While static snapshots of their molecular architecture have been obtained, the shape changes that happen during the transport cycle have not been fully described. Hassane Mchaourab, Ph.D., and colleagues used site-directed spin labeling and electron paramagnetic resonance to capture the dynamics of LeuT, a bacterial version of the mammalian NSS that transports the amino acid leucine. In the July issue of Nature Structural & Molecular Biology, they report the structural changes that facilitate transport, including previously unknown sodium-dependent structural changes in and near the extracellular pocket that binds leucine. The results provide a unique perspective on the dynamic changes associated with transport in an NSS, findings which could be relevant to mood disorders and drug abuse.
— Melissa Marino
Regulatory T cells to the rescue
Graft-versus-host disease (GVHD) is a complication of bone marrow transplantation in which donor immune cells attack recipient tissues (primarily skin, gut and liver). Acute GVHD, occurring within the first 100 days post-transplant, affects more than 50 percent of patients and contributes to transplant mortality.
Immune cells called regulatory T cells (Tregs) have been implicated in the prevention of acute GVHD. Brian Engelhardt, M.D., James Crowe, M.D., and colleagues have now discovered that the ability of Tregs to migrate to target tissues influences the occurrence of acute GVHD. They report in Bone Marrow Transplantation that increased levels of circulating Tregs with skin- or gut-homing characteristics at the time of engraftment (when transplanted cells begin to recover and grow) are associated with prevention of skin and gut GVHD, respectively. The findings suggest that tissue-homing Tregs play a role in preventing organ-specific acute GVHD, and that levels of Tregs could be used to predict which patients will be affected and allow physicians to start tissue-directed immunosuppressive therapies earlier.
— Leigh MacMillan
Predicting HIV drug side effects
Peripheral neuropathy – dysfunction of peripheral nerves that causes absent or painful sensation – is one of the most common neurologic complications of nucleoside reverse transcriptase inhibitors (NRTIs), a type of antiretroviral therapy for HIV/AIDS.
Because patients with diseases involving mitochondrial DNA (mtDNA) mutations often have similar neuropathies, Todd Hulgan, M.D., MPH, and colleagues have looked for variations in mtDNA that might explain susceptibility to peripheral neuropathy in NRTI-treated patients. Previously, they reported an association between a certain mtDNA haplogroup – an mtDNA “signature” shared by a population – and peripheral neuropathy during NRTI treatment in non-Hispanic white persons.
They report in the June 1 issue of the Journal of Infectious Diseases that non-Hispanic blacks who belong to another mtDNA haplogroup (called L1c) are at increased risk of developing peripheral neuropathy when they take NRTIs. Such genetic predictors for NRTI-associated peripheral neuropathy could suggest novel approaches to optimize long-term HIV/AIDS therapy in these patients.
— Leigh MacMillan
Gut lining breakdown in IBD mouse
Inflammatory bowel diseases (IBDs), including Crohn’s disease and ulcerative colitis, affect more than 1.4 million Americans. While the disease origins are poorly understood, some studies suggest that cadherin proteins (which regulate the organization of epithelial tissues like skin and gut lining) and p120 (which regulates the stability of cadherin proteins) may play important roles.
To assess p120’s role in the gut, Albert Reynolds, Ph.D., and colleagues deleted p120 in the small intestine and colon of mice. They found these mice died within three weeks of birth of massive intestinal bleeding caused by defects in “adhesion” (or attachment) between the cells lining the small intestine and colon. The p120-deficient mice also showed an increase in inflammatory cells in the tissue layer beneath the gut lining. The findings, published in the June 1 issue of theJournal of Clinical Investigation show that p120 is essential in maintaining the integrity of the gut lining – and suggest that p120 may play a role in IBDs.
— Melissa Marino
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