Synaptotagmin
Synaptotagmin | |
---|---|
Identifiers | |
Symbol | SYT |
OPM superfamily | 45 |
OPM protein | 3hn8 |
Membranome | 199 |
Synaptotagmins (SYTs) constitute a family of
Functions
Based on their brain/endocrine distribution and biochemical properties, in particular C2 domains of certain synaptotagmins bound to calcium, synaptotagmins were proposed to function as calcium sensors in the regulation of neurotransmitter release and hormone secretion. Although synaptotagmins share a similar domain structure and a high degree of homology in the C2 domains, not all synaptotagmins bind to calcium. In fact, only eight out of the fifteen synaptotagmins are capable of calcium binding. The calcium binding synaptotagmins include synaptotagmins 1, 2, 3, 5, 6, 7, 9, and 10. The remaining seven synaptotagmins do not bind to calcium due to the lack of calcium coordinating residues or spatial orientation of the acidic residues (see the section on C2 domains for details).
Calcium-binding synaptotagmins act as Ca2+ sensors and are involved in both:
- early SNAP-25[5]
- late steps of Ca2+-evoked SNARE complex in the presence of calcium. This is thought to be one of the last steps in exocytosis.[9] Calcium-bound synaptotagmin binding to the SNARE complex, causes the fusion clamp effect of complexin to be released, allowing vesicle fusion to occur and exocytosis to proceed.[10]
Synaptotagmins directly affect the synchronicity of calcium-dependent neurotransmission. While the suppression of Syt1 blocks fast, synchronous neurotransmission, it also enhances slow, asynchronous neurotransmission.[11] On the other hand, suppression of Syt7 hinders the slower, asynchronous release of neurotransmitters. This suggests that synaptotagmin-7 is responsible for mediating a slower form of Ca(2+)-triggered release while the faster release is induced by synaptotagmin-1. These discrepancies illustrate important distinctions between synaptotagmin isoforms and how they underlie the kinetics of neurotransmission and long-term potentiation.
C-terminal C2-domains
The C2 domain is a widely occurring conserved sequence motif of 130-140 amino acid residues, which was first defined as the second constant sequence in
The C2A domain regulates the fusion step of
The C2B domain binds to
Plasticity and Learning
Synaptotagmin variants have been implicated in the enhancement of neural connections, leading to long-term potentiation (LTP) in synapses. The localization of synaptotagmin to the endoplasmic reticulum in the cytoplasm drives the growth of these synapses.[18] Synaptogmins such as Syt1 and Syt7 also play a role in calcium-dependent AMPA receptors exocytosis to the neuron membrane.[19] This process initiates LTP formation and underlies learning. Moreover, synaptotagmins are able to respond to elevated levels of calcium at synapses during single action potentials by further heightening calcium levels via withdrawal from intracellular stores.[18] This leads to a stronger response in the postsynaptic cell.
Other important roles
Synaptotagmins have been shown to regulate exocytosis in other intracellular organelles such as
Apart from the molecular events mediated by synaptotagmins, these proteins have also been identified to play a large role in the cognitive realm. Bipolar disorder is an example of one such instance where synaptotagmins exhibit their effects in a larger context. Knockout of synaptotagmin proteins in animal models elicited both manic and depressive-like symptoms, characteristic of BD.[21] This suggests that synaptotagmin depletion is associated with BD pathology.
Members
- Synaptotagmin 1 (SYT1)
- Synaptotagmin 2 (SYT2)
- Synaptotagmin 3 (SYT3)
- Synaptotagmin 4 (SYT4)
- Synaptotagmin 5 (SYT5)
- Synaptotagmin 6 (SYT6)
- Synaptotagmin 7 (SYT7)
- Synaptotagmin 8 (SYT8)
- Synaptotagmin 9 (SYT9)
- Synaptotagmin 10 (SYT10)
- Synaptotagmin 11 (SYT11)
- Synaptotagmin 12 (SYT12)
- Synaptotagmin 13 (SYT13)
- Synaptotagmin 14 (SYT14)
- Synaptotagmin 15 (SYT15)
- Synaptotagmin 16 (SYT16)
- Synaptotagmin 17 (SYT17)
References and notes
- ISBN 978-0-8493-8528-5.
- PMID 22398727.
- ^ "NIH VideoCast - Ca2+ Sensors for Exocytosis". videocast.nih.gov. Retrieved 16 April 2018.
- ^
Fukuda M, Moreira JE, Liu V, Sugimori M, Mikoshiba K, Llinás RR (December 2000). "Role of the conserved WHXL motif in the C terminus of synaptotagmin in synaptic vesicle docking". Proceedings of the National Academy of Sciences of the United States of America. 97 (26): 14715–9. PMID 11114192.
- PMID 9023371.
- ^
Pang ZP, Melicoff E, Padgett D, Liu Y, Teich AF, Dickey BF, et al. (December 2006). "Synaptotagmin-2 is essential for survival and contributes to Ca2+ triggering of neurotransmitter release in central and neuromuscular synapses". The Journal of Neuroscience. 26 (52): 13493–504. PMID 17192432.
- PMID 16301172.
- S2CID 39531338.
- PMID 16990140.
- PMID 19164751.
- PMID 24267651.
- PMID 12234184.
- ^
Zimmerberg J, Akimov SA, Frolov V (April 2006). "Synaptotagmin: fusogenic role for calcium sensor?". Nature Structural & Molecular Biology. 13 (4): 301–3. S2CID 32067429.
- S2CID 1756258.
- S2CID 12384262.
- ^
Bai J, Tucker WC, Chapman ER (January 2004). "PIP2 increases the speed of response of synaptotagmin and steers its membrane-penetration activity toward the plasma membrane". Nature Structural & Molecular Biology. 11 (1): 36–44. S2CID 1311311.
- PMID 18784080.
- ^ PMID 28882990.
- PMID 28355182.
- PMID 26450452.
- PMID 32041882.
External links
- Synaptotagmins at the U.S. National Library of Medicine Medical Subject Headings (MeSH)