Synapse proteins

Synapse proteins correspond to many human disease genes and dmg targets for therapeutics that modulate cognitive illnesses. 

Another global neuroproteomic study carried out by Collins et al, (unpublished results) focused on the neurophosphoproteome, i.e. the collection of phosphoproteins at the synapse. Protein phosphoiylation is an essential regulator of protein function and signaling mechanisms in any biological system. It has been estimated that one third of all proteins are phosphorylated in the mammalian cell and if it is assumed that one third of all proteins are expressed in the brain, then a conservative estimate of the number of phosphoproteins expressed in the brain would be in the order of... 

Lv C, Gould TJ, Bewersdorf J et al (2012) High-resolution optical imaging of zebrafish larval ribbon synapse protein BIBEYE, BIM2, and CaV 1.4 by stimulation emission depletion microscopy. Microsc Microanal 18 745-752... 

Thus nicotinoids that have the highest insecticidal action have the highest piC and, consequently, exist largely in the ionized form at physiological pH. This produces the anomaly that the compounds that are most highly ionized react most rapidly with the receptor protein, yet they are less able to penetrate through the ionic barrier surrounding the insect nerve synapse. 

GABAb receptors mediate the slow and prolonged physiological effects of the inhibitory neurotransmitter GABA. Functional GABAb receptors are comprised of two subunits, GABAbR1 and GABAbR2. Both subunits are G-protein-coupled receptors, which couple to the Gi/o family and are densely expressed at spinal nociceptive synapses. 

Glutamate is a small amino acid which constitutes the most important neurotransmitter at excitatory synapses in the mammalian brain. Glutamate can act on several different types of receptors including cation channels and G-protein-coupled receptors. 

Synaptic Transmission. Figure 1 Synaptic transmission. The presynaptic terminal contains voltage-dependent Na Superscript and Ca2+ channels, vesicles with a vesicular neurotransmitter transporter VNT, a plasmalemmal neurotransmitter transporter PNT, and a presynaptic G protein-coupled receptor GPCR with its G protein and its effector E the inset also shows the vesicular H+ pump. The postsynaptic cell contains two ligand-gated ion channels LGIC, one for Na+ and K+ and one for Cl-, a postsynaptic GPRC, and a PNT. In this synapse, released transmitter is inactivated by uptake into cells. 

Figure 3.1 Schematic representation of a generic excitatory synapse in the brain. The presynaptic terminal releases the transmitter glutamate by fusion of transmitter vesicles with the nerve terminal membrane. Glutamate diffuses rapidly across the synaptic cleft to bind to and activate AMPA and NMDA receptors. In addition, glutamate may bind to metabotropic G-protein-coupled glutamate receptors located perisynaptically to cause initiation of intracellular signalling via the G-protein, Gq, to activate the enzyme phospholipase and hence produce inositol triphosphate (IP3) which can release Ca from intracellular calcium stores...

As with the other monoamines, 5-HT is found primarily in storage vesicles (30-35 nm diameter) where serotonin-binding proteins (SBPs) have also been identified. These seem to form a macromolecular complex with 5-HT. In fact, three such proteins have now been characterised, but only one of them, 45kDa SBP, appears to be secreted into the synapse along with 5-HT. Whether they serve any role other than forming an osmotically inert storage matrix for 5-HT is unknown. 

Garcia RA, Vasudevan K, Buonanno A 2000 The neuregulin receptor ErbB-4 interacts with PDZ-containing proteins at neuronal synapses. Proc Natl Acad Sci USA 97 3596-3601... 

Haile, C.N., Hiroi, N., Nestler, E.J., Kosten, T.A. Differential behavioral responses to cocaine are associated with dynamics of mesolimbic dopamine proteins in Lewis and Fischer 344 rats. Synapse. 41 179, 2001. 

Striplin, C.D., Kalivas, P.W. Robustness of G protein changes in cocaine sensitization shown with immunoblotting. Synapse. 14 10, 1993. 

Suemaru, J., Akiyama, K., Tanabe, Y., Kuroda, S. Methamphetamine decreases calcium-calmodulin dependent protein kinase II activity in discrete rat brain regions. Synapse. 36 155, 2000. 

Wang, X., Baumann, M.H., Xu, H., and Rothman, R.B., 3,4-Methylenedioxymethamphetamine (MDMA) administration to rats decreases brain tissue serotonin but not serotonin transporter protein and glial fibrillary acidic protein, Synapse 53(4), 240-248, 2004. 

Figure 2.5. The synapse. GPCR = guanine nucleotide-binding protein-coupled receptor, LGICR = ligand-gated ion channel receptor, SB = synaptic bouton, T = neurotransmitter, YOC = voltage-operated ion channel protein, YOCC = voltage-operated calcium channel protein, Ast = astrocyte, AA = axoaxonal synapse, ASD = axosomatic or axodendritic synapse. GPCR 1 = receptor protein, 2 = G-protein, 3 = enzyme, 4 = ion channel protein.

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