Kenakin, T.P. (1995) Agonist-receptor efficacy II: agonist trafficking of receptor signals. Trends Pharmacol. Sci. 16: 232–238CrossRefGoogle ScholarPubMed

Roth, B.L., Chuang, D.-M. (1987) Multiple mechanisms of serotonergic signal transduction. Life Sci. 41: 1051–1064CrossRefGoogle ScholarPubMed

Lawler, C.P., Prioleua, C., Lewis, M.M., Mak, C., Jiang, D., Schetz, J.A., Gonzalez, A.M., Sibley, D.R., and Mailman, R.B. (1999) Interactions of the novel antipsychotic aripiprazole (OPC-14597) with dopamine and serotonin receptor subtypesNeuropsychopharmacol. 20: 612–627CrossRefGoogle ScholarPubMed

Ward, J.S., Merrit, L., Calligaro, D.O., Bymaster, F.P., Shannon, H.E., Sawyer, B.D., Mitch, C.H., Deeter, J.B., Peters, S.C., Sheardown, M.J., Olesen, P.H., Swedberg, M.D.B., and Sauerberg, P. (1995) Functionally selective M1 muscarinic agonists. 3. Side chains and azacycles contributing to functional muscarinic selectivity among pyrazacycles. J. Med. Chem. 38: 3469–3481CrossRefGoogle Scholar

Heldman, E., Barg, J., Fisher, A., Levy, R., Pittel, Z., Zimlichman, R., Kushnir, M. and Vogel, Z. (1996) Pharmacological basis for functional selectivity of partial muscarinic receptor agonists. Eur. J. Pharmacol. 297: 283–291CrossRefGoogle ScholarPubMed

Black, J.W., Leff, P. (1983) Operational models of pharmacological agonist. Proc. R. Soc. Lond. [Biol.] 220:141–162CrossRefGoogle Scholar

Spengler, D., Waeber, C., Pantoloni, C., Holsboer, F., Bockaert, J., Seeburg, P.H., and Journot, L. (1993) Differential signal transduction by five splice variants of the PACAP receptor. Nature 365: 170–175Google ScholarPubMed

Kenakin, T.P., Morgan, P.H. (1989) The theoretical effects of single and multiple transducer receptor coupling proteins on estimates of the relative potency of agonists. Mol. Pharmacol. 35:214–222Google ScholarPubMed

Kenakin, T.P. (2002) Efficacy at G protein coupled receptors. An. Rev. Pharmacol. Toxicol. 42: 349–379CrossRefGoogle ScholarPubMed

Kenakin, T.P. (2003) Ligand-selective receptor conformations revisited: the promise and the problem. Trends Pharmacol. Sci. 24: 346–354CrossRefGoogle ScholarPubMed

Fraunfelder, H., Parak, F., and Young, R.D. (1988) Conformational substrates in proteins. Annu. Rev. Biophys. Biophys. Chem. 17: 451–479CrossRefGoogle Scholar

Fraunfelder, H., Sligar, S.G., and Wolynes, P.G. (1991) The energy landscapes and motions of proteins. Science 254: 1598–1603CrossRefGoogle Scholar

Hilser, V.J., Garcia-Moreno, B., Oas, T.G., Kapp, G., and Whitten, S.T. (2006) A statistical thermodynamic model of the protein ensemble. Chem. Rev. 106: 1545–1558CrossRefGoogle ScholarPubMed

Hilser, V.J., Thompson, E.B. (2007) Intrinsic disorder as a mechanism to optimize allosteric coupling in proteins. Porc. Nat. Acad. Sci. USA 104: 8311–8315CrossRefGoogle ScholarPubMed

Liu, J., Perumal, N.B., Oldfield, J., Su, E.W., Uversky, V.N., Dunker, A.K. (2006) Intrinsic disorder in transcription factors. Biochem. 45: 6873–6888CrossRefGoogle ScholarPubMed

Burgen, A.S.V. (1966) Conformational changes and drug action. Fed. Proc. 40: 2723–2728Google Scholar

Gether, U., Sansan, L., and Kobilka, B.K. (1995) Fluorescent labeling of purified β2-adrenergic receptor: evidence for ligand specific conformational changes. J. Biol. Chem. 270: 28268–28275.Google Scholar

Ghanouni, P., Gryczynski, Z., Steenhuis, J.J., Lee, T.W., Farrens, D.L., Lakowicz, J.R., Kobilka, B.K. (2001) Functionally different agonists produce distinct conformations in G-protein coupling domains of the b2-adrenergic receptor. J. Biol. Chem. 276: 24433–24436CrossRefGoogle Scholar

Hruby, V.J., Tollin, G. (2007) Plasmon-waveguide resonance (PWR) spectroscopy for directly viewing rates of GPCR/G-protein interactions and quantifying affinities. Curr. Opin Pharmacol. 7: 507–514CrossRefGoogle ScholarPubMed

Okada, T., Palczewski, K. (2001) Crystal structure of rhodopsin: implications for vision and beyond. Curr. Opin. Struc. Biol. 11: 420–426CrossRefGoogle ScholarPubMed

Palanche, T., Ilien, B., Zoffmann, S., Reck, M.-P., Bucher, B., Edelstein, S.J., and Galzi, J.-L. (2001) The neurokinin A receptor activates calcium and cAMP responses through distinct conformational states. J. Biol. Chem. 276: 34853–34861CrossRefGoogle ScholarPubMed

Swaminath, G., Xiang, Y., Lee, T.W., Steenhuis, J., Parnot, C., Kobilka, B.K. (2004) Sequential binding of agonists to the β2 adrenoceptor: kinetic evidence for intermediate conformational states. J. Biol. Chem. 279: 686–691CrossRefGoogle ScholarPubMed

Lefkowitz, R.J., Shenoy, S.K. (2005) Transduction of receptor signals by β-arrestins. Science 308: 512–517CrossRefGoogle ScholarPubMed

Luttrell, L.M. (2005) Composition and function of G protein-coupled receptor signalsomes controlling mitogen-activated protein kinase activity. J. Mol. Neurosci. 26: 253–263CrossRefGoogle ScholarPubMed

Tilakaratne, N., Sexton, P.M. (2005) G-protein-coupled receptor-protein interactions: basis for new concepts on receptor structure and function. Clin. Expt. Pharmacol. Physiol. 32: 979–987CrossRefGoogle ScholarPubMed

Wang, Q., Limbird, L.E. (2007) Regulation of alpha(2)AR trafficking and signaling by interacting proteins. Biochem. Pharmacol. 73: 1135–1145CrossRefGoogle ScholarPubMed

Brady, A.E., Limbird, L.E. (2002) G protein-coupled receptor interacting proteins: emerging roles in localization and signal transduction [review]. Cell Signal. 14: 297–309CrossRefGoogle Scholar

Ikezu, T., Okamoto, T., Ogata, E., and Nishimoto, I. (1992) Amino acids constitute a Gi-activator sequence of the α2-adrenergic receptor and have a Phe substitute in the G-protein-activator sequence motif. FEBS Lett. 311: 29–32CrossRefGoogle Scholar

Jones, B.W., Hinkle, P.M. (2008) Arrestin binds to different phosphorylated regions of the thyrotropin-releasing hormone receptor with distinct functional consequences. Mol. Pharmacol. 74: 195–202CrossRefGoogle ScholarPubMed

Hilser, J. and Freire, E. (1997) Predicting the equilibrium protein folding pathway: structure-based analysis of staphylococcal nuclease. Protein Struct. Funct. Bioinform. 27: 171–1833.0.CO;2-J>CrossRefGoogle ScholarPubMed

Hilser, V.J., Dowdy, D., Oas, T.G., and Freire, E. (1998) The structural distribution of cooperative interactions in proteins: analysis of the native state ensemble. Proc. Natl. Acad. Sci. USA 95: 9903–9908CrossRefGoogle ScholarPubMed

Woodward, C., Simon, I., and Tuchsen, E. (1982) Hydrogen exchange and the dynamic structure of proteins. Mol. Cell. Biochem. 48:135–141CrossRefGoogle ScholarPubMed

Woodward, C. (1993) Is the slow-exchange core the protein folding core?Trends Biochem. Sci. 18: 359–360CrossRefGoogle ScholarPubMed

Watson, C., Chen, G., Irving, P.E., Way, J., Chen, W.-J. and Kenakin, T.P. (2000) The use of stimulus-biased assay systems to detect agonist-specific receptor active states: implications for the trafficking of receptor stimulus by agonists. Mol. Pharmacol. 58: 1230–1238CrossRefGoogle ScholarPubMed

Koshland, D.E. (1960) The active site of enzyme action. Adv. Enzymol. 22: 45–97Google ScholarPubMed

Monod, J., Wyamn, J., and Changeux, J.P. (1965) On the nature of allosteric transitions. J. Biol. Chem. 12: 88–118Google ScholarPubMed

Thron, C.D. (1973) On the analysis of pharmacological experiments in terms of an allosteric receptor model. Mol. Pharmacol. 9: 1–9Google ScholarPubMed

Karlin, A. (1967) On the application of ‘a plausible model’ of allosteric proteins to the receptor for acetylcholine. J. Theoret. Biol, 16: 306–320CrossRefGoogle Scholar

Colquhoun, D. (1973) The relationship between classical and cooperative models for drug action. In: A Symposium on Drug Receptors, ed. by Rang, H.P., pp 149–182, Baltimore: University Park Press.

Birdsall, N.J., Hulme, E.C., and Stockton, J.M. (1983) Muscarinic receptor subclasses: allosteric interactions. Cold Spring Harbor Symposia on Quantitative Biology. 48 Pt 1: 53–56CrossRefGoogle ScholarPubMed

Stockton, J.M., Birdsall, N.J., Burgen, A.S., and Hulme, E.C. (1983) Modification of the binding properties of muscarinic receptors by gallamine. Molecul Pharmacol. 23: 551–557Google ScholarPubMed

Jakubik, J., el-Fakahany, E.E. (1997) Positive cooperativity of acetylcholine and other agonists with allosteric ligands on muscarinic acetylcholine receptors. Mol. Pharmacol. 52: 172–179CrossRefGoogle ScholarPubMed

Jakubik, J., Bacakova, L., Lisa, V., el-Fakahany, E.E., and Tucek, S. (1996) Activation of muscarinic acetylcholine receptors via their allosteric binding sites. Proc. Nat Acad Sci USA 93: 8705–8709CrossRefGoogle ScholarPubMed

Black, J.W., Duncan, W.A., and Shanks, R.G. (1965) Comparison of some properties of pronethalol and propranolol. Br. J. Pharmacol. Chemo. 25:577–591CrossRefGoogle ScholarPubMed

Azzi, M., Charest, P.G., Angers, S., Rousseau, G., Kohout, T., Bouvier, M., and Piñeyro, G. (2003) β-arrestin-mediated activation of MAPK by inverse agonists reveals distinct active conformations for G-protein-coupled receptors. Proc. Natl. Acad. Sci. USA 100: 11406–11411CrossRefGoogle ScholarPubMed

Milligan, G. (2003) High-content assays for ligand regulation of G-protein coupled receptors. Drug Disc. Today 8: 579–585CrossRefGoogle ScholarPubMed

Lefkowitz, R.J., Whalen, E.J. (2004) β-arrestins: traffic cops of cell signaling. Curr. Opin. Cell Biol. 16: 162–168CrossRefGoogle ScholarPubMed

Fredriksson, R., Schioth, H.B. (2005) The repertoire of G-protein receptors in fully sequenced genomes. Mol. Pharmacol. 67: 1414–1425CrossRefGoogle ScholarPubMed

Olson, K.R., Eglen, R.M. (2007) Beta galactosidase complementation: a cell-based luminescent assay platform for drug discovery. Assay Drug Dev Technol. 5: 137–144CrossRefGoogle ScholarPubMed

Zhao, X., Jones, A., Olson, K.R., Peng, K., Wehrman, T., Park, A., Mallari, R., Nebalasca, D., Young, S.W., and Xiao, S.-H. (2008) A homogeneous enzyme fragment complementation-based b-arrestin translocation assay for high-throughput screening of G-protein-coupled receptors. J. Biomol. Screen 13: 737–747CrossRefGoogle Scholar

Barnea, G., Strapps, W., Herrada, G., Berman, Y., Ong, J., Kloss, B., Axesl, R., and Lee, K.J. (2008) The genetic design of signaling cascades to record receptor activation. Proc. Natl. Acad. Sci USA 105: 64–69CrossRefGoogle ScholarPubMed

Verkaar, F., Rosmalen, J.W.G., Blomenrohr, M., Koppen, C.J., Blankesteijn, W.M., Smits, J.F.M., and Zaman, G.J.R. (2008) G-protein independent cell-based assays for drug discovery on seven-transmembrane receptors. Biotechnol. Ann. Rev. 14: 253–274CrossRefGoogle ScholarPubMed

Verdonk, E., Johnson, K., McGuinness, R., Leung, G., Chen, Y.-W., Tang, H.R., Michelotti, J.M., and Liu, V.F. (2006) Cellular dielectric spectroscopy: a label-free comprehensive platform for functional evaluation of endogenous receptors. Assay Drug Dev. Technol. 4: 609–619CrossRefGoogle ScholarPubMed

McGuinness, R. (2007) Impedance-based cellular assay technologies: recent advances. Curr. Opin. Pharmacol. 7: 535–540CrossRefGoogle ScholarPubMed

Peter, M.F., Knappenberger, K.S., Wilkins, D., Sygowski, L.A., Lazor, L.A., Liu, J., and Scott, C.W. (2007) Evaluation of cellular dielectric spectroscopy, a whole-cell label-free technology for drug discovery on Gi-coupled GPCRs. J. Biomol. Screen 12: 312–319CrossRefGoogle Scholar

Fang, Y., Ferrie, A.M., Fontaine, N.H., and Yuen, P.K. (2005) Characteristics of dynamic mass redistribution of EGF receptor signaling in living cells measured with label free optical biosensors. Anal. Chem. 77: 5720–5725CrossRefGoogle ScholarPubMed

Fang, Y., Li, G., and Peng, J. (2005) Optical biosensor provides insights for bradykinin B2 receptor signaling in A431 cells. FEBS Lett 579: 6365–6374CrossRefGoogle ScholarPubMed

Fang, Y. (2006) Label-free cell-based assays with optical biosensors in drug discovery. Assay Drug Dev. Technol. 4: 583–595CrossRefGoogle ScholarPubMed

Cunningham, B.T., Li, P., Schultz, S., Lin, B., Baird, C., Gerstenmaier, J., et al. (2004) Label free assays on the BIND system. J Biomolec. Screen. 9: 481–490CrossRefGoogle ScholarPubMed

Yu, N., Atienza, J.M., Bernard, J., Blanc, S., Zhu, J., Wang, X., et al. (2006) Real-time monitoring of morphological changes in living cells by electronic cell sensor assays: an approach to study G-protein coupled receptors. Anal. Chem. 78: 35–43CrossRefGoogle ScholarPubMed

Fang, Y., Ferrie, A.M., Fontaine, N., Mauro, J., and Balikrishnan, J. (2006) Resonant waveguide grating biosensors for living cell sensing. Biophys. J. 91: 1925–1940CrossRefGoogle ScholarPubMed

Whistler, J.L., Zastrow, M. (1998) Morphine-activated opioid receptors elude desensitization by β-arrestin. Proc. Nat. Acad. Sci. USA 95: 9914–9919CrossRefGoogle ScholarPubMed

Zhang Jie Zhang, Ferguson, S.S.G., Brak, L.S., Bodduluri, S.R., Laporte, S.A., Law, P-Y., and Caron, M.G. (1998) Role for G protein-coupled receptor kinase in agonist-specific regulation of μ-opioid receptor responsiveness. Proc. Natl. Acad. Sci. USA 95: 7157–7162CrossRefGoogle Scholar

Bailey, C. P., Couch, D., Johnson, E., Griffiths, K., Kelly, E., and Henderson, G. (2003) µ-Opioid receptor desensitization in mature rat neurons: lack of interaction between DAMGO and morphine. J. Neurosci. 23: 10515–10520CrossRefGoogle Scholar

Bohn, L.M., Dykstra, L.A., Lefkowitz, R.J., Caron, M.G., and Barak, L.S. (2004) Relative opioid efficacy is determined by the complements of the G protein coupled receptor desensitization machinery. Mol. Pharmacol. 66: 106–112CrossRefGoogle ScholarPubMed

Koch, T., Widera, A., Bartzsch, K., Schulz, S., Brandenburg, L.-O., Wundrack, N., Beyer, A., Grecksch, G., and Höllt, V. (2005) Receptor endocytosis counteracts the development of opioid tolerance. Mol. Pharmacol. 67: 280–287CrossRefGoogle ScholarPubMed

Stephenson, R.P. (1956) A modification of receptor theory. Br. J. Pharmacol. 11: 379–393Google ScholarPubMed

Furchgott, R.F. (1966) The use of b-haloalkylamines in the differentiation of receptors and in the determination of dissociation constants of receptor-agonist complexes. In Advances in Drug Research, vol 3 ed. by Harper, N.J. and Simmonds, A.B., pp 21–55, Academic Press, London, New York

Berg, K.A. et al. (1998) Effector pathway-dependent relative efficacy at serotonin type 2A and 2C receptors: evidence for agonist-directed trafficking of receptor stimulus. Mol. Pharmacol. 54, 94–104CrossRefGoogle ScholarPubMed

Kenakin, T.P. (2009) 7TM receptor allostery: putting numbers to shapeshifting proteins. Trends Pharmacol. Sci. (in press)CrossRefGoogle ScholarPubMed

Kohout, T.A., Nicholas, S.L., Perry, S.J., Reinhart, G., Junger, S., and Struthers, R.S. (2004) Differential desensitization, receptor phosphorylation, β-arrestin recruitment, and ERK1/2 activation by the two endogenous ligands for the CC chemokine receptor 7. J Biol Chem. 279: 23214–23222CrossRefGoogle ScholarPubMed

Mailman, R.B. (2007) GPCR functional selectivity has therapeutic impact. Trends Pharmacol Sci. 28: 390–397CrossRefGoogle ScholarPubMed

Schmid, C.L., Raehal, K.M., and Bohn, L.M. (2008) Agonist-directed signaling of the serotonin 2A receptor depends on β-arrestin-2 interactions in vivo. Proc Natl Acad Sci USA 105: 1079–1084CrossRefGoogle ScholarPubMed

Vassart, G., Dumont, D. (1992)The thyrotropin receptor and the regulation of thyrocyte function and growth. Endocr Rev. 13: 596–611Google Scholar

Mazzocchi, G., Malendowicz, L.K., Aragona, F., and Nussdorfer, G.G. (2001) Human pheochromocytomas express orexin receptor type 2 gene and display an in vitro secretory response to orexins A and B. J Clin Endocrinol Metab. 86: 4818–4821CrossRefGoogle Scholar

Mazzocchi, G., Malendowicz, L.K., Gottardo, A.F., and Nussdorfer, G.G. (2001) Orexin A stimulates cortisol secretion from human adrenocortical cells through activation of the adenylate cyclase-dependent signaling cascade. J Clin Endocrinol Metab. 86: 778–782CrossRefGoogle ScholarPubMed

Mathiesen, J.M., Ulven, T., Martini, L., Gerlach, L.O., Heineman, A., and Kostenis, E. (2005) Identification of indole derivatives exclusively interfering with a G protein-independent signaling pathway of the prostaglandin D2 receptor CRTH2. Mol Pharmacol. 68: 393–402Google Scholar

Maillet, E.L., Pellegrini, N., Valant, C., Bucher, B., Hibert, M., Bourguignon, J-J., and Galzi, J-L. (2007) A novel, conformation-specific allosteric inhibitor of the tachykinin NK2 receptor (NK2R) with functionally selective properties. FASEB J 21: 2124–2134.CrossRefGoogle ScholarPubMed