SYT1

Fig1. Schematic of Synaptotagmin structure. (Josh V Vermaas, 2017)

What is SYT1 protein?

SYT1 (synaptotagmin 1) gene is a protein coding gene which situated on the long arm of chromosome 12 at locus 12q21. This gene encodes a member of the synaptotagmin protein family. The synaptotagmins are integral membrane proteins of synaptic vesicles that serve as calcium sensors in the process of vesicular trafficking and exocytosis. The encoded protein participates in triggering neurotransmitter release at the synapse in response to calcium binding. The SYT1 protein is consisted of 422 amino acids and its molecular mass is approximately 47.6 kDa.

What is the function of SYT1 protein?

SYT1 is a membrane protein found primarily on the synaptic vesicles of neurons and is essential for regulating the release of neurotransmitters. It is a member of the calcium-sensitive protein family that responds to changes in calcium ion concentration within cells. When the action potential reaches the nerve endings, the intracellular calcium concentration increases, and SYT1 binds to calcium ions through its C2 domain, thus promoting the fusion of synaptic vesicles with the presynaptic membrane, triggering the quantized release of neurotransmitters. This process is the basis for rapid synaptic transmission and is essential for the function of the nervous system. In addition to its role in synaptic transmission, SYT1 is also involved in regulating the endocytosis and recycling of synaptic vesicles, ensuring that the effective release of neurotransmitters can be sustained.

SYT1 Related Signaling Pathway

SYT1 binds to calcium ions through its C2 domain, thereby sensing changes in intracellular calcium concentration. When the action potential reaches the nerve endings, the voltage-gated calcium channel opens and the local calcium ion concentration increases. SYT1 senses this change and causes the vesicles to fuse with the cell membrane, triggering the release of neurotransmitters. Therefore, the signaling pathway involved in SYT1 is mainly the signaling pathway of neurotransmitter release, including classical synaptic transmission processes and some mechanisms related to synaptic plasticity, such as short-term and long-term potentiation (STP and LTP).

Fig2. A model for the role of E-SYT1 as a link between the ER and vesicle-mediated secretion of cytosolic proteins. (Kohji Yamada, 2022)

SYT1 Related Diseases

Diseases associated with this protein include: neuropsychiatric disorders such as Parkinson's disease, Huntington's disease, autism spectrum disorder, and schizophrenia. In Parkinson's disease, mutations in SYT1 are associated with neuronal dysfunction and cell death. Huntington's disease is associated with abnormal aggregation of SYT1 and neuronal death. The occurrence of disorders such as autism spectrum disorder and schizophrenia may be related to the role of SYT1 in neuronal signaling.

Bioapplications of SYT1

SYT1 is widely used as a marker to study synaptic transmission mechanisms, especially in exploring the molecular mechanisms of anchoring and fusion of synaptic vesicles and neurotransmitter release. In addition, manipulating SYT1 expression or function by means of genetic engineering is used to develop neuroscience models to better understand the function and disease of the nervous system.

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.

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