SYT1

Case study 1: Mazdak M Bradberry, 2020

At neuronal synapses, synaptotagmin-1 (SYT1) acts as a Ca2+ sensor that synchronizes neurotransmitter release with Ca2+ influx during action potential firing. Heterozygous missense mutations in SYT1 have recently been associated with a severe but heterogeneous developmental syndrome, termed SYT1-associated neurodevelopmental disorder. Well-defined pathogenic mechanisms, and the basis for phenotypic heterogeneity in this disorder, remain unknown. Here, the researchers report the clinical, physiological, and biophysical characterization of three SYT1 mutations from human patients. Synaptic transmission was impaired in neurons expressing mutant variants, which demonstrated potent, graded dominant-negative effects. Biophysical interrogation of the mutant variants revealed novel mechanistic features concerning the cooperative action, and functional specialization, of the tandem Ca2+-sensing domains of SYT1. These mechanistic studies led to the discovery that a clinically approved K+ channel antagonist is able to rescue the dominant-negative heterozygous phenotype. The results establish a molecular cause, basis for phenotypic heterogeneity, and potential treatment approach for SYT1-associated neurodevelopmental disorder.

Fig1. Average traces of evoked IPSCs from neurons expressing no SYT1 (KO), WT, or mutant SYT1 variants.

Fig2. Representative immunoblot and loading control (CBB: Coomassie Brilliant Blue) for SYT1 quantification experiments.

Case study 2: Joao Miguel Cordeiro, 2013

A low-affinity Ca²⁺/H⁺-antiport was described in the membrane of mammalian brain synaptic vesicles. Electrophysiological studies showed that this antiport contributes to the extreme brevity of excitation-release coupling in rapid synapses. Synaptotagmin-1, a vesicular protein interacting with membranes upon low-affinity Ca²⁺-binding, plays a major role in excitation-release coupling, by synchronizing calcium entry with fast neurotransmitter release. Here, the researchers report that synaptotagmin-1 is necessary for expression of the vesicular Ca²⁺/H⁺-antiport. They measured Ca²⁺/H⁺-antiport activity in vesicles and granules of pheochromocytoma PC12 cells by three methods: (i) Ca²⁺-induced dissipation of the vesicular H⁺-gradient; (ii) bafilomycin-sensitive calcium accumulation and (iii) pH-jump-induced calcium accumulation. The results were congruent and highly significant: Ca²⁺/H⁺-antiport activity is detectable only in acidic organelles expressing functional synaptotagmin-1. In contrast, synaptotagmin-1-deficient cells--and cells where transgenically encoded synaptotagmin-1 was acutely photo-inactivated--were devoid of any Ca²⁺/H⁺-antiport activity. Therefore, in addition to its previously described functions, synaptotagmin-1 is involved in a rapid vesicular Ca²⁺ sequestration through a Ca²⁺/H⁺ antiport.

Fig3. Experiment carried out on post-nuclear supernatant (PNS) from PC12 G11(+/+) cells, which spontaneously express SYT1.

Fig4. The Ca2+ ionophore, ionomycin, induces a non-specific calcium uptake, which does not depend on SYT-1.

Fig1. Evoked and spontaneous glutamate release, resulting in a balance between extracellular and intracellular glutamate pools. (Annette Vaglio-Garro, 2024)

Fig2. The PERK/E-SYT1 complex promotes lipid transport to mitochondria and the maintenance of mitochondrial functions in human cells. (Sébastien Leterme, 2023)

SYT1 involved in several pathways and played different roles in them. We selected most pathways SYT1 participated on our site, such as Synaptic vesicle cycle, which may be useful for your reference. Also, other proteins which involved in the same pathway with SYT1 were listed below. Creative BioMart supplied nearly all the proteins listed, you can search them on our site.

SYT1 has several biochemical functions, for example, 1-phosphatidylinositol binding, SNARE binding, calcium ion binding. Some of the functions are cooperated with other proteins, some of the functions could acted by SYT1 itself. We selected most functions SYT1 had, and list some proteins which have the same functions with SYT1. You can find most of the proteins on our site.

SYT1 has direct interactions with proteins and molecules. Those interactions were detected by several methods such as yeast two hybrid, co-IP, pull-down and so on. We selected proteins and molecules interacted with SYT1 here. Most of them are supplied by our site. Hope this information will be useful for your research of SYT1.

IKBKG; CACNB4; IKBKG; Syt1; ZDHHC17; PCBD1; TFCP2; CBFB; SMAD2; CACNB3; GOLM1; Caskin1; SNAPIN; Slc14a2; EPS15; STON2; COPS4