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Research Round-up

Posted by on Wednesday, March 1, 2017 in Around the Medical Center, Winter 2017 .

Reducing antidepressants’ side effects

Medicines used to treat depression, called selective serotonin reuptake inhibitors (SSRIs), can increase bleeding risk and bleeding time and disrupt platelet aggregation in the gastrointestinal tract. SSRIs prevent cells from taking up the neurotransmitter serotonin that has been released from cells by blocking the serotonin transporter (SERT). It is unclear how blocking SERT disrupts platelet aggregation.

Heidi Hamm, Ph.D., Ana Carneiro, Ph.D., and colleagues used pharmacological and genetic models to show that chronic SSRI treatment causes decreased levels of a serotonin receptor (5-HT2AR) on platelets. They showed that inhibiting SERT increases extracellular serotonin, which desensitizes the 5-HT2AR and reduces platelet activation.

These findings, reported in the Journal of Biological Chemistry, suggest a novel mechanism where prolonged use of SSRI medications results in reduced platelet aggregation. This provides useful insight into the effects of SSRIs and supports findings that drugs targeting the serotonin receptor may be used to reduce recurrent thrombosis by blocking platelet activation.

This research was supported by grants from the National Institutes of Health (MH090256, TR000445, TR000446, TR000447, MH084659) and by an American Heart Association Predoctoral Fellowship Award.



Building the basement membrane  

Work by Billy Hudson, Ph.D., and colleagues has helped establish the critical role that the enzyme peroxidasin plays in the development of tissues throughout the animal kingdom.

Peroxidasin catalyzes the formation of the sulfilimine crosslinks between collagen IV molecules, a major constituent of the basement membrane. The basement membrane, in turn, undergirds cell layers and reinforces the structural integrity of nearly all animal tissues.

Little is known, however, about what regulates the activity of this essential enzyme.

Now, in the Journal of Biological Chemistry, Selen Colon and Gautam Bhave, M.D., Ph.D., report that another enzyme family, the pro-protein convertases, cleaves peroxidasin in a way that enhances its catalytic activity and promotes the formation of sulfilimine crosslinks.

“Processing” by pro-protein convertases is a widespread form of enzyme regulation. In this case, cleavage of peroxidasin produces a powerful oxidant, hydrobromous acid.

This research was supported by a grant from the National Institutes of Health (DK097306), a Burroughs Wellcome Fund Career Award for Medical Scientists, and developmental funds from the Vanderbilt University Division of Nephrology and Hypertension.



Stem cells promote tolerance

Permanent acceptance of organ transplants requires “immune tolerance,” and studies have suggested that hematopoietic stem cells (HSCs, blood-forming cells in the bone marrow) may play a role in tolerance induction.

Daniel Moore, M.D., Ph.D., and colleagues have now demonstrated that mobilization of HSCs is required for transplantation tolerance in a mouse model of type 1 diabetes— and that HSC activity depends on a functioning sympathetic nervous system. Disruption of either HSC mobilization or the sympathetic nervous system resulted in failure of tolerance to transplants of insulin-producing pancreatic islets.

The investigators found that excess expression of the receptor CXCR4 held HSCs in the bone marrow, and that blocking this receptor mobilized HSCs and prolonged islet transplant survival.

The findings were reported in the journal Diabetes.