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J. Biol. Chem., Vol. 278, Issue 11, 9258-9266, March 14, 2003

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The C2A Domain of Synaptotagmin Alters the Kinetics of Voltage-gated Ca²⁺ Channels Ca_v1.2 (Lc-type) and Ca_v2.3 (R-type)^*

Roy Cohen, Lisa A. Elferink^§, and Daphne Atlas^¶

From the  Department of Biological Chemistry, The Hebrew University of Jerusalem, Jerusalem 91904, Israel and the ^§ Department of Physiology & Biophysics and the Marine and Biomedical Institute, University of Texas Medical Branch, Galveston, Texas 77555-1069

Biochemical and genetic studies implicate synaptotagmin (Syt 1) as a Ca²⁺ sensor for neuronal and neuroendocrine neurosecretion. Calcium binding to Syt 1 occurs through two cytoplasmic repeats termed the C2A and C2B domains. In addition, the C2A domain of Syt 1 has calcium-independent properties required for neurotransmitter release. For example, mutation of a polylysine motif (residues 189-192) reverses the inhibitory effect of injected recombinant Syt 1 C2A fragment on neurotransmitter release from PC12 cells. Here we examined the requirement of the C2A polylysine motif for Syt 1 interaction with the cardiac Ca_v1.2 (L-type) and the neuronal Ca_v2.3 (R-type) voltage-gated Ca²⁺ channels, two channels required for neurotransmission. We find that the C2A polylysine motif presents a critical interaction surface with Ca_v1.2 and Ca_v2.3 since truncated Syt 1 containing a mutated motif (Syt 1*_1-264) was ineffective at modifying the channel kinetics. Mutating the polylysine motif also abolished C2A binding to Lc_753-893, the cytosolic interacting domain of Syt 1 at Ca_v1.2 1 subunit. Syt 1 and Syt 1* harboring the mutation at the KKKK motif modified channel activation, while Syt 1* only partially reversed the syntaxin 1A effects on channel activity. This mutation would interfere with the assembly of Syt 1/channel/syntaxin into an exocytotic unit. The functional interaction of the C2A polylysine domain with Ca_v1.2 and Ca_v2.3 is consistent with tethering of the secretory vesicle to the Ca²⁺ channel. It indicates that calcium-independent properties of Syt 1 regulate voltage-gated Ca²⁺ channels and contribute to the molecular events underlying transmitter release.

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