Differential distribution of synGAP alpha1 and synGAP beta isoforms in rat neurons.

The synaptic Ras-GTPase activating protein synGAP is a brain-specific protein of approximately 130 kDa and is a negative regulator of Ras. We previously reported 5 C-terminal isoforms of synGAP (alpha1, alpha2, beta1/2, beta 3/4 and gamma) [Li et al., 2001, J. Biol. Chem. 276: 21417-21424]. In this study, we investigated the expression profiles of the two major isoforms, synGAP alpha1 and synGAP beta, in the adult rat brain and cultured neurons of the rat hippocampus. Examination of pepsin-pretreated brain sections demonstrated that both isoforms were expressed mainly in the forebrain structures, which suggests their association with postsynaptic density. The distribution of the synGAP alpha1 and beta (beta1-4) isoforms in the adult rat brain was clearly different in cerebellum, hippocampus, cerebral cortex, septum and olfactory bulb. In particular, synGAP alpha1 was specifically localized to the cerebellar glomeruli, dense synaptic sites. From the analysis using cultured neurons, unique expression of synGAP beta was found in a neuron with a sea urchin-like morphology, possibly a star pyramidal neuron, in which the synGAP beta expression was relatively high, in particular, at the distal part of its processes. SynGAP alpha1 was mostly or specifically localized to excitatory postsynaptic sites, whereas synGAP beta was present at both excitatory and inhibitory postsynaptic sites. Finally, there are more non-synaptic clusters in dendrites in the case of synGAP beta than synGAP alpha1. Thus, the two synGAP isoforms, alpha1 and beta, distribute differently in neuronal cells and the brain.