Mechanisms Of Recruitment

While we are gradually beginning to understand mechanisms by which postsynaptic components are transported, the more important issue of how postsynaptic transport packets are trapped at nascent synaptic sites remains largely unknown. A large amount of research is currently being directed toward cell adhesion molecules as initiators of synapse formation (see Chapters 4-10). In fact, two classes of cell adhesion molecules have been found to be highly synaptogenic: Neuroligins and SynCAMs (see Chapters 7 and 8). However, the exact mechanism by which these single-transmembrane molecules transduce contact and adhesion to bring about the recruitment of pre- and postsynaptic molecules and organelles is still a mystery. Possibilities include interactions with MAGUK proteins via PDZ binding domains and the binding of actin filaments.

Even understanding the recruitment of diffusible PSD-95 to Neuroligin, which can interact with each other directly84, presents conceptual problems or at least numerous possibilities to be tested. Presumably, PSD-95 can only bind to Neuroligin when Neuroligin is bound to its presynaptic partner, Neurexin. For this to be the case, one can imagine a change in conformation in the cytoplasmic tail of Neuroligin which could open up the C-terminal PDZ binding domain, allowing PSD-95 to bind. On the other hand, one could envisage a mechanism by which binding of Neurexin to Neuroligin transmits a signal to palmitoyl transferases, which can then palmitoylate PSD-9 5 85,86. This modification anchors PSD-95 at the plasma membrane and is necessary for the localization of PSD-95 to synapses17. This modification could enhance binding of PSD-95 to the PDZ binding domain of Neuroligin directly by a morphological change or by reducing the diffusional space to a two-dimensional area87.

In the case of membrane receptors being transported along microtubules in vesicles the problem of recruitment becomes even more complex. First of all we must establish whether recruitment of such transport packets occurs by directed movement or by generation of a stop signal. In the case of directed movement, we have to imagine a diffusible second messenger such as calcium or cAMP which would originate from the site of presynaptic contact and cause molecular motors to move up the gradient. The stop signal could also involve a diffusible molecule, but would need to cause motor proteins to stop once above a threshold concentration. This signal could be constituted by a kinase or a phosphatase. Another mechanism is illustrated by the study showing that intracellular domains of NCAM may provide a trapping signal via a direct interaction with proteins coating intracellular organelles, such as P1-spectrin82. In addition it seems that the switches in proteinprotein associations between glutamate receptors and scaffolding proteins, mentioned above, could also help "stop" or "direct" transport packets to new sites of synapse formation. However, the mechanisms involved remain completely unkown.

Interestingly, it appears that a signal for the recruitment of AMPA receptors has been found. AMPA receptors appear at synapses with a delay with respect to NMDA receptors9. These data together with the finding that glutamatergic synapses are largely "silent," NMDA-only synapses early in development8,67,68, spurred the hypothesis that strong activation of these synapses would recruit AMPA receptors to the postsynaptic membrane, as seen in paradigms of long-term potentiation (LTP) at mature synapses66. Recent evidence points to the activation of NMDA receptors by glutamate at nascent synapses as being a trigger for AMPA receptor recruitment88. Similarly to the induction of LTP89, the recruitment of AMPA receptors to new synapses is mediated by calcium/calmodulin-dependent protein kinase II (CaMKII), since transfection of a constitutively active form of CaMKII increased colocalization of AMPA receptors with Neurexin-induced PSD-95 clusters88 (see Figure 14.2; Colorplate 9). Further mechanisms of how CaMKII directs AMPA receptors to the nascent synaptic site remain to be explored.

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