Trafficking phosphorylation

This experimental drug is a derivative of myriocin. After phosphorylation FTY720 modulates chemotactic responses and lymphocyte trafficking, leading to reversible lymphocyte sequestration in secondary lymphoid tissues. It is in clinical trials for the treatment of multiple sclerosis. 

Recent evidence indicates that the 5-HT transporter is subject to post-translational regulatory changes in much the same way as neurotransmitter receptors (Blakeley et al. 1998). Protein kinase A and protein kinase C (PKC), at least, are known to be involved in this process. Phosphorylation of the transporter by PKC reduces the Fmax for 5-HT uptake and leads to sequestration of the transporter into the cell, suggesting that this enzyme has a key role in its intracellular trafficking. Since this phosphorylation is reduced when substrates that are themselves transported across the membrane bind to the transporter (e.g. 5-HT and fi -amphetamine), it seems that the transport of 5-HT is itself linked with the phosphorylation process. Possibly, this process serves as a homeostatic mechanism which ensures that the supply of functional transporters matches the demand for transmitter uptake. By contrast, ligands that are not transported (e.g. cocaine and the selective serotonin reuptake inhibitors (SSRIs)) prevent the inhibition of phosphorylation by transported ligands. Thus, such inhibitors would reduce 5-HT uptake both by their direct inhibition of the transporter and by disinhibition of its phosphorylation (Ramamoorthy and Blakely 1999). 

Blakely, RD, Ramamoorthy, S, Schroeter, S, Qian, Y, Apparsundaram, S, Galli, A and DeFelice, LJ (1998) Regulated phosphorylation and trafficking of antidepressant-sensitive serotonin transporter proteins. Biol. Psychiatry 44 169-178. 

Upon activation, neurons begin trafficking TRPVl to the membrane where the receptors become activated, desensitized and then recycled to the intracellular compartments. Translocation of TRPVl to the cell membrane occurs via SNARE (snapin and synaptotagmin IX)-mediated exocytosis [37]. Broadly speaking, activation involves phosphorylation by protein kinases (most notably, protein kinase A [PKA] and C [PKC]) and desensitization involves de-phosphorylation by phosphatases (e.g. calcineurin) [38]. Among PKC isozymes, PKCp seems to be of particular importance [39]. 

Arden JR, Segredo V, Wang Z et al. Phosphorylation and agonist-specific intracellular trafficking of an epitope-tagged K-opioid receptor expressed in HEK 293 cells. J Neurochem 1995 65 1636-1645. 

Hallett, P. J., Spoelgen, R., Hyman, B. T., Standaert, D. G. and Dunah, A. W. (2006). Dopamine D1 activation potentiates striatal NMDA receptors by tyrosine phosphorylation-dependent subunit trafficking. J. Neurosci. 26, 4690-700. 

Min, L., and Ascoli, M. (2000) Effect of activating and inactivating mutations on the phosphorylation and trafficking of the human lutropin/choriogonadotropin receptor. Mol. Endocrinol. 14, 1797-1810. 

Bdlingsley, M.L., Kincaid, R.L. (1997) Regulated phosphorylation and dephosphorylation of tan protein effects on microtubule interaction, intracellular trafficking and neurodegeneration. Biochem. J., 323, 577-591. 

Oh M. C., Derkach V. A., Guire E. S., and Soderling T. R. (2006). Extrasynaptic membrane trafficking regulated by GluRl serine 845 phosphorylation primes AMPA receptors for long-term potentiation. J. Biol. Chem. 281 752-758. 

Viviani B., Gardoni F., Bartesaghi S., Corsini E., Facchi A., Galli C. L., Di Luca M., and Marinovich M. (2006). Interleukin-1 released by gpl20 drives neural death through tyrosine phosphorylation and trafficking of NMDA receptors. J. Biol. Chem. 281 30212-30222. 

---