Psd95

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PSD-95 is a member of the membrane-associated guanylate kinase (GK) homologs (MAGUKs), which lack an ATP-binding site and consequently do not have kinase enzymatic activity. PSD-95 possesses three PDZ domains, which provide a platform for postsynaptic anchoring of NMDARs, kainate receptors and neuroligin, one Src-homology domain 3 (SH3), which provides a binding site for synaptic GTPase-activating protein (SynGAP), and finally one GK domain, which mediates interaction with the guanylate kinase-associated protein (GKAP) that enhances postsynaptic recruitment of group I mGluRs through the intermediates Shank and Homer. In line with this, overexpression of PSD-95 was shown to accelerate the development and size of glutamatergic synapses and furthermore to promote the maturation of contacting presynaptic terminals, probably due to a retrograde neuroligin signal66. The postsynaptic recruitment of PSD-95 is controlled by MAPK phosphorylation45. The Ras GTPase-activating protein SynGAP, which binds to the SH3 domain in PSD-95, negatively regulates MAPK activation, but is itself under negative control of CaMKII67. This implies that NMDAR activation and concomitant Ca2+ influx leads to CaMKII-mediated inhibition of SynGAP and thereby enhances MAPK-dependent signaling, which enhances postsynaptic PSD-95 recruitment (Table 1).

It should be considered here that the functional output of CaMKII with respect to NMDAR efficacy renders CaMKII a key candidate for the treatment of chronic and in particular neuropathic pain disorders. In addition, postsynaptic recruitment of PSD-95 is controlled by tyrosine phosphorylation of P-catenin, which mediates interactions between the cell adhesion molecule cadherin and the actin cyto-skeleton. In that case, however, tyrosine phosphorylation of P-catenin negatively affects the differentiation of postsynaptic domains. Schuman and colleagues proposed that depolarization by glutamatergic synaptic activity drives a signaling

Table 1. Summary of the Effects of Protein Phosphorylation on the Composition and Functional Adjustment of Postsynaptic Proteomes at Glutamatergic and GABAergic Synapses. The mode of action (T: enhancement, reduction) of a few selected protein kinases on neurotransmitter receptors, anchoring proteins, and cell adhesion molecules is shown. For details on the underlying mechanisms see Sections 4.1 and 4.2. References are given in brackets. (*) in this study, the number of glutamatergic synaptic profiles (dendritic spines) was unaffected by modulation of TrkB receptor signaling, however, TrkB receptor signaling promoted maturation or "activation" of excitatory synapses, which explains the increase in the number of functional glutamatergic synapses.

Table 1. Summary of the Effects of Protein Phosphorylation on the Composition and Functional Adjustment of Postsynaptic Proteomes at Glutamatergic and GABAergic Synapses. The mode of action (T: enhancement, reduction) of a few selected protein kinases on neurotransmitter receptors, anchoring proteins, and cell adhesion molecules is shown. For details on the underlying mechanisms see Sections 4.1 and 4.2. References are given in brackets. (*) in this study, the number of glutamatergic synaptic profiles (dendritic spines) was unaffected by modulation of TrkB receptor signaling, however, TrkB receptor signaling promoted maturation or "activation" of excitatory synapses, which explains the increase in the number of functional glutamatergic synapses.

Kinase

Phosphorylation Target

Consequences on

Effect

Synapse Number Glu GABA

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