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

Research output: Contribution to journalArticle

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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.

Original languageEnglish
Article number900
Number of pages9
JournalNature Communications
Volume3
DOIs
Publication statusPublished - 12 Jun 2012

Fingerprint

GTPase-Activating Proteins
Protein Isoforms
Alternative Splicing
proteins
splicing
Proteins
Protein C
Transcriptome
Synapses
Complementary DNA
Neurons
Amplification
synapses
Demonstrations
primers
Peptides
Genes
Modulation
loci
neurons

Keywords

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

Cite this

McMahon, A. C., Barnett, M. W., O'Leary, T. S., Stoney, P. N., Collins, M. O., Papadia, S., ... Kind, P. C. (2012). SynGAP isoforms exert opposing effects on synaptic strength. Nature Communications, 3, [900]. https://doi.org/10.1038/ncomms1900

SynGAP isoforms exert opposing effects on synaptic strength. / 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.

In: Nature Communications, Vol. 3, 900, 12.06.2012.

Research output: Contribution to journalArticle

McMahon, AC, Barnett, MW, O'Leary, TS, Stoney, PN, Collins, MO, Papadia, S, Choudhary, JS, Komiyama, NH, Grant, SGN, Hardingham, GE, Wyllie, DJA & Kind, PC 2012, 'SynGAP isoforms exert opposing effects on synaptic strength', Nature Communications, vol. 3, 900. https://doi.org/10.1038/ncomms1900
McMahon AC, Barnett MW, O'Leary TS, Stoney PN, Collins MO, Papadia S et al. SynGAP isoforms exert opposing effects on synaptic strength. Nature Communications. 2012 Jun 12;3. 900. https://doi.org/10.1038/ncomms1900
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. / SynGAP isoforms exert opposing effects on synaptic strength. In: Nature Communications. 2012 ; Vol. 3.
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