Oxidative protein modification of soluble N‐ethylmaleimide‐sensitive factor attachment protein receptors

Abstract

Evidence suggests that bipolar disorder is a progressive disease with imbalanced neurotransmission. Recent studies indicated that mitochondrial dysfunction is associated with this disorder. Mitochondria are enriched in the synaptic terminals. Mitochondrial dysfunction is the major source for production of reactive oxygen species that may induce oxidative modification of synaptic proteins. Soluble N‐ethylmaleimide‐sensitive factor attachment protein receptors (SNAREs), including synaptosomal‐associated protein 25 (SNAP25), syntaxin and synaptobrevin, play critical roles in neurotransmission. Using immunoprecipitation followed by immunoblotting analysis, we found that hydroxyl radical increased carbonylation of SNAP25 and syntaxin in rat cerebral cortex. Using co‐immunoprecipitation, we found that hydroxyl radical decreased interaction between SNAP25 and syntaxin. In addition, we found that 4‐hydroxynonenal (4‐HNE), an end product of lipid peroxidation, can form protein adducts with SNAP25 in rat cerebral cortex. We also found that chronic treatment with mood stabilizing drug lithium inhibited 4‐HNE‐SNAP25 adduction. Since SNAP25, syntaxin and synaptobrevin form SNARE protein complex that plays a significant role in neurotransmitter release, our results suggest that oxidative modification of these proteins may contribute to imbalanced neurotransmission in bipolar disorder.