The Synaptotagmin C2A Domain Is Part of the Calcium Sensor Controlling Fast Synaptic Transmission

Neuron. 2003 Jul 17;39(2):299-308. doi: 10.1016/s0896-6273(03)00432-x.


Synaptotagmin is a synaptic vesicle protein that has been proposed to be the calcium sensor responsible for fast neurotransmitter release at synapses. Synaptotagmin's two C2 domains, C2A and C2B, each provide a calcium binding pocket lined with negative charges contributed by five conserved aspartates. We find that even when all of C2A's conserved aspartates are neutralized by replacement with asparagines, neurotransmitter release still occurs at hippocampal synapses in culture. Because exocytosis continues to be dependent on extracellular calcium concentration, the C2A domain cannot represent the entire calcium sensor. C2A does appear to be part of the calcium sensor, however, because substitution of D232 alters the calcium dependence of release, perhaps by reducing the number of calcium ions that must bind to trigger exocytosis. We conclude that neutralization of the negative charge at D232 by coordination of a calcium ion is necessary--but not sufficient--for fast neurotransmission at mammalian CNS synapses.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Alcohol Oxidoreductases
  • Animals
  • Arginine / genetics
  • Aspartic Acid / genetics
  • Binding Sites
  • Calcium / metabolism*
  • Calcium-Binding Proteins*
  • Cells, Cultured
  • Dose-Response Relationship, Drug
  • Electrophysiology
  • Embryo, Mammalian
  • Excitatory Postsynaptic Potentials / genetics
  • Hippocampus / physiology
  • Magnesium / metabolism
  • Membrane Glycoproteins / classification
  • Membrane Glycoproteins / physiology*
  • Mice
  • Mice, Knockout
  • Nerve Tissue Proteins / classification
  • Nerve Tissue Proteins / physiology*
  • Neurons / metabolism
  • Neurons / physiology*
  • Protein Structure, Tertiary / physiology*
  • Recovery of Function / genetics
  • Synaptic Transmission / physiology*
  • Synaptotagmin II
  • Synaptotagmins
  • Transfection / veterinary


  • Calcium-Binding Proteins
  • Membrane Glycoproteins
  • Nerve Tissue Proteins
  • Synaptotagmin II
  • Syt2 protein, mouse
  • Synaptotagmins
  • Aspartic Acid
  • Arginine
  • Alcohol Oxidoreductases
  • lactate-malate transhydrogenase
  • Magnesium
  • Calcium