CUED Publications database

SynGAP isoforms exert opposing effects on synaptic strength.

McMahon, AC and Barnett, MW and O'Leary, TS and Stoney, PN and Collins, MO and Papadia, S and Choudhary, JS and Komiyama, NH and Grant, SGN and Hardingham, GE and Wyllie, DJA and Kind, PC (2012) SynGAP isoforms exert opposing effects on synaptic strength. Nat Commun, 3. 900-.

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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.

Item Type: Article
Uncontrolled Keywords: Amino Acid Sequence Animals Electrophysiology Hippocampus Mass Spectrometry Mice Mice, Inbred C57BL Molecular Sequence Data Neurons Protein Isoforms Synapses ras GTPase-Activating Proteins
Divisions: Div F > Control
Depositing User: Cron Job
Date Deposited: 17 Jul 2017 19:07
Last Modified: 09 Sep 2021 00:36
DOI: 10.1038/ncomms1900