SynGAP isoforms exert opposing effects on synaptic strength

A C McMahon, M W Barnett, T S O'Leary, P N Stoney, M O Collins, S Papadia, J S Choudhary, N H Komiyama, S G N Grant, G E Hardingham, D J A Wyllie, P C Kind

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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.

Original languageEnglish
Article number900
Number of pages9
JournalNature Communications
Publication statusPublished - 12 Jun 2012


  • amino acid sequence
  • animals
  • electrophysiology
  • hippocampus
  • mass spectrometry
  • mice
  • mice, inbred C57BL
  • molecular sequence data
  • neurons
  • protein isoforms
  • synapses
  • ras GTPase-activating proteins

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    McMahon, A. C., Barnett, M. W., O'Leary, T. S., Stoney, P. N., Collins, M. O., Papadia, S., Choudhary, J. S., Komiyama, N. H., Grant, S. G. N., Hardingham, G. E., Wyllie, D. J. A., & Kind, P. C. (2012). SynGAP isoforms exert opposing effects on synaptic strength. Nature Communications, 3, [900].