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SynGAP isoforms exert opposing effects on synaptic strength

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    Rights statement: This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 3.0 Unported License. © 2012 Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved. partner of AGORA, HINARI, OARE, INASP, ORCID, CrossRef and COUNTER

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http://www.nature.com/ncomms/journal/v3/n6/full/ncomms1900.html
Original languageEnglish
Article number900
Number of pages9
JournalNature Communications
Volume3
DOIs
Publication statusPublished - Jun 2012

Abstract

Alternative promoter usage and alternative splicing enable diversification of the transcriptome. Here we demonstrate that the function of Synaptic GTPase-Activating Protein (SynGAP), a key synaptic protein, is determined by the combination of its amino-terminal sequence with its carboxy-terminal sequence. 5' rapid amplification of cDNA ends and primer extension show that different N-terminal protein sequences arise through alternative promoter usage that are regulated by synaptic activity and postnatal age. Heterogeneity in C-terminal protein sequence arises through alternative splicing. Overexpression of SynGAP α1 versus α2 C-termini-containing proteins in hippocampal neurons has opposing effects on synaptic strength, decreasing and increasing miniature excitatory synaptic currents amplitude/frequency, respectively. The magnitude of this C-terminal-dependent effect is modulated by the N-terminal peptide sequence. This is the first demonstration that activity-dependent alternative promoter usage can change the function of a synaptic protein at excitatory synapses. Furthermore, the direction and degree of synaptic modulation exerted by different protein isoforms from a single gene locus is dependent on the combination of differential promoter usage and alternative splicing.

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