Fine-tuned protein makes memories
The enzyme CaMKII is a central player in the neuronal signaling that builds memories. Precise control of CaMKII activity depends on proteins such as densin, a “scaffolding” protein that assembles multiprotein complexes at sites of neuronal signaling.
Roger Colbran, Ph.D., and colleagues have discovered new features of the CaMKII-densin interaction. They report in the Journal of Biological Chemistry that densin can interact with multiple CaMKII types in mouse brain and cultured cells. They identified a novel binding site for CaMKII in an internal region of the densin protein and found that this densin-IN domain is 50 percent similar to a known CaMKII inhibitor protein. The densin-IN domain and the full densin protein inhibited CaMKII’s ability to phosphorylate (modify) one type of excitatory glutamate receptor (AMPA), but not another type (NMDA).
The findings suggest a unique mechanism for fine-tuning CaMKII activity toward different targets, which could play a role in the synaptic plasticity that underlies learning and memory.
— Leigh MacMillan
Cocaine and the teenage brain
Experimentation with drugs is common during the teen years. But the consequences of exposure to drugs like cocaine during this critical period for brain development remain unclear.
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To understand how cocaine affects the developing adolescent brain, Christine Konradi, Ph.D., Stephanie Sillivan, and colleagues administered escalating doses of cocaine to “teenage” rats over a 12-day period – a model of “binge” cocaine exposure. When the rats reached adulthood, cocaine-exposed animals displayed decreased anxiety and fear-related learning – and increased levels of novelty-seeking – compared to untreated animals. The investigators also analyzed gene expression changes in the amygdala – the brain region involved in the processing and memory of emotional events – and found that genes belonging to pathways involved in brain development and wiring were affected.
The results, published in Biological Psychiatry, suggest that cocaine exposure during adolescence may lead to mis-wiring in the developing brain and result in long-lasting behavioral problems, such as increased risk-taking, in adulthood.
— Melissa Marino
Inflammation relief: what’s the delay?
Glucocorticoids are steroid hormones that suppress inflammatory responses in the body. Synthetic versions of these hormones are used clinically to treat conditions like arthritis and asthma, but their anti-inflammatory effects can take from four to 24 hours after administration to kick in.
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Previously, Sandip Bhattacharyya, Ph.D., and colleagues showed that glucocorticoids regulate different signaling pathways depending on the activation of various Toll-like receptors (TLRs), the immune “sensors.” But since these events happen early in the inflammatory process, other mechanisms must be involved in the delayed effects of glucocorticoids. In the June 7 issue of the Proceedings of the National Academy of Sciences, they report that the delayed effects may result from the regulated activation of two other factors – SOCS1 and type I interferons – several hours after the initial activation of TLRs.
The results obtained from SOCS1-deficient macrophages suggest that augmenting SOCS1 action could provide the anti-inflammatory benefits of glucocorticoids without inducing the adverse side effects associated with steroid treatments.
— Melissa Marino
Antioxidant genes keep stomach moving
Gastroparesis – delayed emptying of the stomach that can cause indigestion, recurrent vomiting and abdominal pain – affects up to 40 percent of patients with diabetes, and is more frequent in women.
As part of the Meharry-Vanderbilt Alliance, Pandu Gangula, Ph.D., at Meharry Medical College, with VUMC collaborators Michael Freeman, Ph.D., and Sekhar Konjeti, Ph.D., investigated the role of oxidative stress in gastroparesis. The investigators studied mice missing the gene for the protein NRF2, a transcription factor that directs the expression of multiple antioxidant genes, or GCLM, a regulator of the antioxidant glutathione.
They report in Free Radical Biology & Medicine that mice missing NRF2 or GCLM have deficient nitric oxide-mediated gastric motility, and they characterize the functional and biochemical changes in the generation of nitric oxide. The findings demonstrate that loss of antioxidant gene expression can contribute to the development of gastroparesis and suggest that antioxidant genes may be good therapeutic targets for the disorder.
— Leigh MacMillan
We welcome suggestions for research to highlight in Aliquots. The items should be primary research articles (no reviews, editorials or commentaries) published within the last two months in a peer-reviewed journal. Please send the article citation (PDF if available) and any other feedback about the column to: aliquots@vanderbilt.edu.
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