Synaptotagmins form a hierarchy of exocytotic Ca2+ sensors with distinct Ca2+ affinities

Shuzo Sugita, Ok Ho Shin, Weiping Han, Ye Lao, Thomas C. Südhof

Research output: Contribution to journalArticle

193 Citations (Scopus)

Abstract

Synaptotagmins constitute a large family of membrane proteins implicated in Ca2+-triggered exocytosis. Structurally similar synaptotagmins are differentially localized either to secretory vesicles or to plasma membranes, suggesting distinct functions. Using measurements of the Ca2+ affinities of synaptotagmin C2-domains in a complex with phospholipids, we now show that different synaptotagmins exhibit distinct Ca2+ affinities, with plasma membrane synaptotagmins binding Ca2+ with a 5- to 10-fold higher affinity than vesicular synaptotagmins. To test whether these differences in Ca2+ affinities are functionally important, we examined the effects of synaptotagmin C2-domains on Ca2+-triggered exocytosis in permeabilized PC12 cells. A precise correlation was observed between the apparent Ca2+ affinities of synaptotagmins in the presence of phospholipids and their action in PC12 cell exocytosis. This was extended to PC12 cell exocytosis triggered by Sr2+, which was also selectively affected by high-affinity C2-domains of synaptotagmins. Together, our results suggest that Ca2+ triggering of exocytosis involves tandem Ca2+ sensors provided by distinct plasma membrane and vesicular synaptotagmins. According to this hypothesis, plasma membrane synaptotagmins represent high-affinity Ca2+ sensors involved in slow Ca2+dependent exocytosis, whereas vesicular synaptotagmins function as low-affinity Ca2+ sensors specialized for fast Ca2+-dependent exocytosis.

Original languageEnglish (US)
Pages (from-to)270-280
Number of pages11
JournalEMBO Journal
Volume21
Issue number3
DOIs
StatePublished - Feb 1 2002
Externally publishedYes

Fingerprint

Synaptotagmins
Exocytosis
Sensors
Cell membranes
PC12 Cells
Cell Membrane
Phospholipids
Secretory Vesicles

Keywords

  • C-domain
  • Ca binding protein
  • Exocytosis
  • Neurotransmitter release
  • Synaptic plasticity

ASJC Scopus subject areas

  • Genetics
  • Cell Biology

Cite this

Synaptotagmins form a hierarchy of exocytotic Ca2+ sensors with distinct Ca2+ affinities. / Sugita, Shuzo; Shin, Ok Ho; Han, Weiping; Lao, Ye; Südhof, Thomas C.

In: EMBO Journal, Vol. 21, No. 3, 01.02.2002, p. 270-280.

Research output: Contribution to journalArticle

Sugita, Shuzo ; Shin, Ok Ho ; Han, Weiping ; Lao, Ye ; Südhof, Thomas C. / Synaptotagmins form a hierarchy of exocytotic Ca2+ sensors with distinct Ca2+ affinities. In: EMBO Journal. 2002 ; Vol. 21, No. 3. pp. 270-280.
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