Syt itself does not catalyze lipid
Syt1 itself does not catalyze lipid mixing and membrane fusion. Rather, the pairing of vesicular and target membrane SNAREs into complexes serves to pull bilayers together to drive fusion; Ca•syt1 accelerates these fusion reactions so that they occur on rapid timescales in a manner that is precisely synchronized with increases in [Ca]. Syt1 physically interacts with SNAREs, and in the presence of acidic lipids Ca•syt1 can drive the assembly of stable SNARE complexes . These observations provide an appealing connection between the Ca sensor for pik 2 and the core of the membrane fusion machinery. However, findings concerning correlations between the ability of syt1 mutants to bind SNAREs and to drive release have been mixed, and this remains an open question.
In summary, the work of Brose . represents the first study to show that syt1 binds Ca and negatively charged phospholipids. Twenty-six years later, these robust and reproducible observations have come to define two of the key steps in Ca-triggered exocytosis: Ca sensing and the ensuing rapid fusion of SVs with the plasma membrane.
The author thanks M.M. Bradberry for the artwork shown in Figure 1, Figure 2. Structure and surface renderings were generated using UCSF Chimera. This work was supported by grants from the National Institutes of Health (MH061876 and NS097362 to E.R.C.). E.R.C. is an Investigator of the Howard Hughes Medical Institute.
Introduction Oxidative stress is an imbalance of systemic manifestation resulting from accumulation of reactive oxygen species (ROS) [1,2]. It is a critical pathological factor in various diseases including neurodegenerative diseases, cardiovascular disease and age-related cancer, etc. [3,4]. Evidence have showed that oxidative stress results in an increased production of peroxides and free radicals and promotes protein nitration, lipid peroxidation, mitochondrial dysfunction, inflammatory responses and cell apoptosis [5,6]. Therefore, oxidative stress presents a deleterious effect on cell survivals. Oxidative stress is associated with mitochondrial dysfunction, which is a main reason causing cell death . Mitochondrial is generally considered as a cellular power factory because of ATP generation. The production of ATP is extremely important in energy metabolism, which is referred as the molecular unit of currency of intracellular energy transfer . In addition, ATP is also involved in intracellular signaling. It serves as a substrate for kinases, enzymes and adenylate cyclase, what’s more, it can trigger calcium (Ca2+) signals by releasing Ca2+ from intracellular stores [, , ]. Once intracellular ATP balance is destroyed, cells will be threatened with death. In oxidative stress, ROS emission from mitochondria can induce further ROS release from neighboring mitochondria and deplete the mitochondrial antioxidative defense, which is ROS-induced ROS release [12,13]. Excessive oxidative phosphorylation in mitochondria contributes to a large quantity of ROS generation, which induces the mitochondrial DNA (mtDNA) damage and further leads to mitochondrial dysfunction . Mitochondrial dysfunction induced by oxidative stress plays a critical role in intracellular ATP level decrease and cell damage [15,16]. Our previous study found an interesting phenomenon that the extracellular ATP was significantly increased after oxidative stress induced by H2O2. It intrigued us to explore the pathway which mediated the increase of extracellular ATP level. Increasing evidence show that lysosomes are involved in ATP release extracellularly in response to different stimulation [, , , ]. Lysosomes are involved in various cell processes including degradation, phagocytosis, plasma membrane repairing and cell signaling [21,22]. Extracellular treatment of ATP, glutamate, and potassium cyanide can induce lysosomes exocytosis, which contains ATP molecules, and Ca2+ is necessary and sufficient during this process. Moreover, lysosomes have different modes of exocytosis that contribute to the intercellular signaling under different pathological conditions .