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The Journal of Neuroscience, January 11, 2006, 26(2):632-643; doi:10.1523/JNEUROSCI.2589-05.2006

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Cellular/Molecular
Different Effects on Fast Exocytosis Induced by Synaptotagmin 1 and 2 Isoforms and Abundance But Not by Phosphorylation

Gábor Nagy,¹ Jun Hee Kim,¹ Zhiping P. Pang,² Ulf Matti,³ Jens Rettig,³ Thomas C. Südhof,² and Jakob B. Sørensen¹

¹Max-Planck-Institute for Biophysical Chemistry, D-37077 Göttingen, Germany, ²Center for Basic Neuroscience, Department of Molecular Genetics, and Howard Hughes Medical Institute, The University of Texas Southwestern Medical Center, Dallas, Texas 75390, and ³Institute of Physiology, Saarland University, D-66421 Homburg, Germany

Synaptotagmins comprise a large protein family, of which synaptotagmin 1 (Syt1) is a Ca²⁺ sensor for fast exocytosis, and its close relative, synaptotagmin 2 (Syt2), is assumed to serve similar functions. Chromaffin cells express Syt1 but not Syt2. We compared secretion from chromaffin cells from Syt1 null mice overexpressing either Syt isoform. High time-resolution capacitance measurement showed that Syt1 null cells lack the exocytotic phase corresponding to the readily-releasable pool (RRP) of vesicles. Comparison with the amperometric signal confirmed that the missing phase of exocytosis consists of catecholamine-containing vesicles. Overexpression of Syt1 rescued the RRP and increased its size above wild-type values, whereas the size of the slowly releasable pool decreased, indicating that the availability of Syt1 regulates the relative size of the two releasable pools. The RRP was also rescued by Syt2 overexpression, but the kinetics of fusion was slightly slower than in cells expressing Syt1. Biochemical experiments showed that Syt2 has a slightly lower Ca²⁺ affinity for phospholipid binding than Syt1 because of a difference in the C2A domain. These data constitute evidence for the function of Syt1 and Syt2 as alternative, but not identical, calcium-sensors for RRP fusion. By overexpression of Syt1 mutated in the shared PKC/calcium/calmodulin-dependent kinase phosphorylation site, we show that phorbol esters act independently and upstream of Syt1 to regulate the size of the releasable pools. We conclude that exocytosis from mouse chromaffin cells can be modified by the differential expression of Syt isoforms and by Syt abundance but not by phosphorylation of Syt1.

Key words: chromaffin cell; exocytosis; membrane capacitance; synaptotagmin 1 and 2; phosphorylation; protein kinase C

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Received June 23, 2005; revised November 16, 2005; accepted November 18, 2005.

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