Protein Kinases and Protein Recruitment at Glutamatergic Synapses

4.1.1. Receptor Diffusion

To date it is well established that neurotransmitter receptors are mobile entities, which can bind and unbind to postsynaptic anchor proteins. Therefore, the classical static view of postsynaptic receptor distributions was challenged by the discovery that postsynaptic receptor numbers fluctuate as a consequence of receptor flux into and out of synapses. In fact, Choquet and colleagues provided the first insights into the dynamics underlying postsynaptic neurotransmitter receptor anchoring. They could nicely show that the lateral mobility of glycine receptors (GlyRs) is characterized by ultrafast alternations between two states, diffusive and confined57. The following studies confirmed this dynamic view of the glycinergic postsynaptic apparatus, and GlyR movements were characterized more in detail, at the single molecule level58. The perception of the synapse as a highly dynamic structure was further extended to other neurotransmitter receptor systems, such as AMPARs59 and GABAARs60,61. Therefore, by shifting this equilibrium between diffusive and confined receptor diffusion states protein kinases exert major effects on the postsynaptic responsiveness.

4.1.2. PDZ Domains

The most common protein-protein interaction motive present in the postsynaptic proteome of glutamatergic synapses is the PDZ domain. PDZ domains can occur several times within the same protein and, thus, are well suited to cross-link synaptic proteome constituents. Therefore, they are considered to constitute the building blocks in the assembly of pre- and postsynaptic proteomes. As described elsewhere (Chapter 4), PSD-95, glutamate receptor interacting protein (GRIP), and Homer are among the so-called scaffolding molecules responsible for the postsynaptic anchoring of NMDARs and kainate receptors, AMPARs, and metabotropic glutamate receptors (mGluRs), respectively.

Intriguingly, the serine/threonine residues within the amino acid motives (S/TXV, S/T: serine or threonine, X: any amino acid, V: hydrophobic amino acid) capable of binding to PDZ domains are protein kinase substrates. So far, however, little is known about the potential impact that phosphorylation of the PDZ domain recognition motives may exert on protein-protein interaction. Some recent evidence suggests that phosphorylation of the threonine residue within PDZ recognition motives enhances its binding capacity62. Others have shown that phosphorylation of the PDZ recognition motive exerts a negative effect on proteinprotein interaction. For example, the interaction of the potassium inward rectifying channel (Kir)2.3 with PSD-95 is reduced by PKA phosphorylation of the serine residue within the Kir2.3 PDZ domain recognition motive. By reducing the availability of postsynaptic Kir2.3 channels, which hyperpolarize the membrane potential, PKA might help to facilitate relief of the Mg2+ block from NMDARs63. Furthermore, Kim and colleagues showed that PKA phosphorylation of the PDZ domain recognition sequence of stargazin, a protein that contributes to postsynaptic AMPAR targeting, reduces its interaction with PSD-95, which interferes with postsynaptic delivery of AMPARs64. Beyond this, PKA was found to contribute to postsynaptic AMPAR delivery through direct phosphorylation of AMPA receptor type 1 (GluR1)-containing AMPARs by facilitating its re-insertion into the plasma membrane after endocytosis. This, however, requires a concomitant Ca2+ entry through NMDARs65 and may therefore involve additional kinases, such as CaMKII (see below).

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