SynGAP isoforms exert opposing effectson synaptic strength

摘要

Alternative promoter usage and alternative splicing enable diversification of the transcriptome.Here we demonstrate that the function of synaptic GTPase-Activating Protein (synGAP), akey synaptic protein, is determined by the combination of its amino-terminal sequence with itscarboxy-terminal sequence. 5′ rapid amplification of cDnA ends and primer extension showthat different n-terminal protein sequences arise through alternative promoter usage that areregulated by synaptic activity and postnatal age. Heterogeneity in C-terminal protein sequencearises through alternative splicing. overexpression of synGAP alpha 1 versus alpha 2 C-termini-containingproteins in hippocampal neurons has opposing effects on synaptic strength, decreasingand increasing miniature excitatory synaptic currents amplitude/frequency, respectively.The magnitude of this C-terminal-dependent effect is modulated by the n-terminal peptidesequence. This is the first demonstration that activity-dependent alternative promoter usagecan change the function of a synaptic protein at excitatory synapses. Furthermore, the directionand degree of synaptic modulation exerted by different protein isoforms from a single genelocus is dependent on the combination of differential promoter usage and alternative splicing.