Receptor oligomerization

Besides cytoplasmic protein kinases, membrane receptors can exert protein kinase activity. These so-called receptor tyrosine kinases (RTK) contain a ligandbinding extracellular domain, a transmembrane motif, and an intracellular catalytic domain with specificity for tyrosine residues. Upon ligand binding and subsequent receptor oligomerization, the tyrosine residues of the intracellular domain become phosphory-lated by the intrinsic tyrosine kinase activity of the receptor [3, 4]. The phosphotyrosine residues ftmction as docking sites for other proteins that will transmit the signal received by the RTK. 

Suzuki S, Chuang LE, Yau P, Doi RH, Chuang RY (2002b) Interactions of opioid and chemokine receptors oligomerization of mu, kappa, and delta with CCR5 on immune cells. Exp Cell Res 280 192-200... 

George, S. R., Lee, S. P, Varghese, G Zeman, P. R., Seeman, P., Ng, G. Y., and O Dowd, B. F. (1998) A transmembrane domain-derived peptide inhibits D1 dopamine receptor function without affecting receptor oligomerization../. Biol. Chem. 273, 30244-30248. 

Schulz, A., Grosse, R., Schultz, G., Gudermann, T., and Schoneberg, T. (2000) structural implication for receptor oligomerization from functional reconstitution studies of mutant V2 vasopressin receptors. J. Biol. Chem. 275, 2381-2389. 

G-protein-coupled receptor oligomerization and its potential for drug discovery. Nature Reviews Drug discovery, 1, 808-820. 

Nichol and Winzor described the binding equations that apply to such hgand-induced changes in receptor oligomerization. They also presented the following equation to describe the joint operation of allosteric ligand binding cooperativity and receptor self-association. 

Lemmon, A. and Schlessinger, I Regulation of signal transduction and signal diversity by receptor oligomerization (1994) Trends Bioch. Sd. 19, 459- 463... 

Frank, S., Lustig, A., Schulthess, T., Engel, J., and Kammerer, R. A. (2000). A distinct seven-residue trigger sequence is indispensable for proper coiled-coil formation of the human macrophage scavenger receptor oligomerization domain./. Biol. Chem. 275, 11672-11677. 

H3 receptors are hetereogeneous for three reasons species differences in amino acid sequence and, hence, pharmacology (Zaragoza et al. 2004) receptor oligomerization (Bakker 2004) and the existence of, so far, six splice variants, H3A, H3B, H3C, H3D, H3E, and H3F (Bakker et al. 2006). The latter three variants, H3D, H3E, and H3F, are retained intracellularly and may control the cell surface expression of H3A, H3B, and H3C. Since most reports on histamine receptor modulation of transmitter release only refer to the H3 receptor, not to the splice variants, I do not differentiate between these in the following. 

Wells JA (1994) Structural and functional basis for hormone binding and receptor oligomerization, Curr Opin Cell Biol, 6 163-173... 

McVey M, Ramsay D, Kellett E, Rees S, Wilson S, et al. 2001. Monitoring receptor oligomerization using time-resolved fluorescence resonance energy transfer and bioluminescence resonance energy transfer. The human delta-opioid receptor displays constitutive oligomerization at the cell... 

Breitwieser, G. E. (2004). G protein-coupled receptor oligomerization Implications for G protein activation and cell signaling. Circ. Res. 94, 17-27. 

Floyd, D. H., Geva, A., Bruinsma, S. P., Overton, M. C., Blumer, K.J., and Baranski, T. J. (2003). C5a receptor oligomerization. II. Fluorescence resonance energy transfer studies of a human G protein-coupled receptor expressed in yeast. J. Biol. Chem. 278, 35354-35361. 

Since Rluc and GEP recombinantly fused proteins can be expressed in living cells, BRET is an interesting tool for monitoring molecular interactions in cell-based assays. BRET has been particularly used for the study of GPCRs by probing receptor oligomerization or activation. ... 

Both M6P receptors have been noted to form oligomers. Cross-linking of soluble CD-MPR and IGF-II/CI-MPR have demonstrated that receptor oligomerization depends upon pH, receptor concentration, and the presence or absence of ligand [154,155,156]. The on-off rates of association are relatively fast, indicating that oligomerization is a process in dynamic equilibrium. 

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