The current catalog of PSD proteins, and the diversity of signaling pathways that contribute to spine formation and PSD assembly, present a rather diverse picture of cellular activities which shape formation of the postsynaptic specialization. If one takes into account the promiscuity of the protein/protein interactions engaged by the various signaling proteins, it is at present rather difficult to assess the contribution of individual proteins. Thus rac or cdc42 can bind to quite a number of downstream target proteins, and it is not known which of these targets are present during dendrite development and spine formation at significant quantities. The same holds true for signaling intermediates such as IRSp53, which may control a substantial variety of dendritic actin regulatory proteins as well as postsynaptic scaffolds. The case of the rac target Sra-1/CYFIP is particularly intriguing: does it control the actin nucleation activity of WAVE in dendrites, or the translational inhibitory activity of FMRP? If it does both, does the lack of FMRP in MR patients lead to a loss of translation control, or does it simply mean that more Sra-1/CYFIP is available to inhibit WAVE? Methods providing subcellular quantification of possible binding partners should help in this respect. At the microscopic level fluorescence methods enabling temporal and spatial resolution are required to understand when and where a particular signaling event might occur. In this respect, the detection of local activation of rac by the FRET probes employed by Zhang and colleagues36 is an interesting development which should be applicable to other signaling pathways.
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