Synaptotagmin I functions as a calcium regulator of release probability

Fernández-Chacón, Rafael
Königstorfer, Andreas
Gerber, Stefan H.
García, Jesús
Matos, Maria F.
Stevens, Charles F.
Brose, Nils
Rizo, Josep
Rosenmund, Christian
Südhof, Thomas C.

*Center for Basic Neuroscience, Department of Molecular Genetics, and Howard Hughes Medical Institute, The University of Texas Southwestern Medical Center, Dallas, Texas 75390-9111, USA
§Max-Planck-Institut für experimentelle Medizin, and †Max-Planck-Institut für biophysikalische Chemie, 37070 Göttingen, Germany
∥Departments of Biochemistry and Pharmacology, The University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA
❡The Salk Institute, and Howard Hughes Medical Institute, La Jolla, California 92037, USA

‡These authors contributed equally to this work

Received 9 October; accepted 12 December 2000.

Correspondence and requests for materials should be addressed to T.C.S.

Nature 410(6824):p 41-49, March 1, 2001.

In all synapses, Ca²⁺ triggers neurotransmitter release to initiate signal transmission. Ca²⁺ presumably acts by activating synaptic Ca²⁺ sensors, but the nature of these sensors-which are the gatekeepers to neurotransmission-remains unclear. One of the candidate Ca²⁺ sensors in release is the synaptic Ca²⁺-binding protein synaptotagmin I. Here we have studied a point mutation in synaptotagmin I that causes a twofold decrease in overall Ca²⁺ affinity without inducing structural or conformational changes. When introduced by homologous recombination into the endogenous synaptotagmin I gene in mice, this point mutation decreases the Ca²⁺ sensitivity of neurotransmitter release twofold, but does not alter spontaneous release or the size of the readily releasable pool of neurotransmitters. Therefore, Ca²⁺ binding to synaptotagmin I participates in triggering neurotransmitter release at the synapse.