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Synaptotagmin: A Ca2+ sensor that triggers exocytosis?

Key Points

  • Neuronal exocytosis is triggered by Ca2+ ions, and members of the synaptotagmin gene family (>13 isoforms) are leading candidates to serve as the Ca2+ sensors that trigger neurotransmitter release. Synaptotagmin I is the best characterized isoform, and is the most abundant Ca2+-binding protein on secretory organelles.

  • Genetic studies indicate that synaptotagmin I functions at several stages in the synaptic-vesicle cycle, including a key function between the docking and fusion of vesicles, which is consistent with its proposed role as a Ca2+ sensor during exocytosis. Synaptotagmin I also has a key role in endocytosis after fusion.

  • The structures of the Ca2+-sensing domains of synaptotagmin — C2A and C2B — and the Ca2+-binding sites of these domains have been determined.

  • Studies are now beginning to uncover how Ca2+ regulates the interaction of synaptotagmin with effectors. Ca2+ triggers the partial penetration of the Ca2+-binding loops of the C2 domains of synaptotagmin into lipid bilayers with very rapid kinetics. Penetration into the plasma membrane might pull bilayers together to facilitate fusion.

  • The C2 domains of synaptotagmin also interact directly with components of the SNARE complex, which is thought to form the core of a conserved membrane fusion machine. These interactions might facilitate the assembly of SNARE complexes to accelerate fusion.

  • Efforts at present are directed towards the reconstitution of Ca2+-triggered membrane fusion. A defined and reduced model system might make it possible to determine whether synaptotagmin is a Ca2+ sensor that triggers exocytosis.

Abstract

It has been fifty years since the discovery that Ca2+ triggers the rapid exocytosis of neurotransmitters from neurons. One of the proteins that has a crucial role in this secretion event is synaptotagmin I, an abundant constituent of synaptic vesicles that binds Ca2+ ions through two C2 domains. These properties prompted the idea that synaptotagmin I might function as a Ca2+-sensor that triggers neurotransmitter release. So does synaptotagmin trigger exocytosis in a Ca2+-dependent manner, and, if so, how does it operate?

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Figure 1: The synaptic-vesicle cycle.
Figure 2: The structure of synaptotagmin.
Figure 3: Detailed model of synaptotagmin–membrane interactions.
Figure 4: A model for synaptotagmin function during exocytosis.

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DATABASES

Interpro

C2 domains

LocusLink

AMPA

Swiss-Prot

calmodulin

complexin I

complexin II

cytosolic phospholipase A2

Munc13

p65

SNAP-25

SV2

synaptotagmin III

synaptotagmin IV

synaptotagmin VII

Vam7

Glossary

ACTION POTENTIAL

A propagating impulse of voltage in excitable cells.

ACTIVE ZONES

Electron-dense regions in the presynaptic plasma membrane, onto which synaptic vesicles dock and fuse.

PRIMING

A series of reactions that are required to make secretory vesicles competent for fusion.

LARGE DENSE CORE VESICLES

Relatively large (≥100 nm) secretory vesicles that are released with slower kinetics than synaptic vesicles, and that often contain peptide hormones.

V0 SECTOR

The membrane-associated part of the vacuolar H+-ATPase, which is composed of five different subunits (a, d, c, c′ and c″).

VACUOLAR H+-ATPASE

A proton pump that controls the pH of many intracellular compartments.

EC50 VALUE

The concentration of an agent at which a half-maximal effect is observed.

FLASH PHOTOLYSIS OF CAGED Ca2+

A technique in which Ca2+ is sequestered into a 'cage' until the cage is destroyed by a pulse of light, which gives rise to a rapid increase in the free Ca2+ concentration.

EF-HAND

A graphical description for the structure of a Ca2+-binding motif that was first described in parvalbumin (for review, see Ref. 129).

HYPOMORPHS

Mutations that cause a partial loss of function of a given gene or protein.

INTRAGENIC COMPLEMENTATION

A situation in which a heterozygote carrying two different mutations that affect the same polypeptide has a phenotype that is closer to the wild-type than that of either of the respective homozygotes. In most cases, this results from effects on subunit interactions in multimeric proteins.

ZWITTERIONIC LIPIDS

Lipids that carry both positive and negative charges.

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Chapman, E. Synaptotagmin: A Ca2+ sensor that triggers exocytosis?. Nat Rev Mol Cell Biol 3, 498–508 (2002). https://doi.org/10.1038/nrm855

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