Cloning of receptors

The evaluations to determine relevant species for toxicity evaluation include various receptor binding assays and tissue cross-reactivity assessments, the later being routinely performed for monoclonal antibody based products (see Chapters 10 and 26). Species specificity can be determined using properly controlled in vitro cell-based response assays, cloning of receptors and ligands to determine compatibility, receptor-based response assays, immunoassays, genomic-based assays, and traditional biochemical-based assays as well as in vivo assessments with validated endpoints and markers for specificity. 

The molecular cloning of receptors that bind to neuropeptide Y (NPY) and its related peptides, peptide YY (PYY) and pancreatic polypeptide (PP), has advanced somewhat more slowly than for many other peptide receptors. Even after the Y1 receptor was cloned (Herzog et al., 1992 Krause et al., 1992 Larhammar et al., 1992) progress has been modest despite expectations from pharmacological studies for up to six more receptor genes, i.e. receptor-types Y2 and Y3 as well as receptors for appetite , PYY, PP and PP-fold peptides. At last, reports from several laboratories described clones for additional receptor subtypes, namely the Y2 receptor and a PP receptor, also called Y4 (see Table 1 for all sequence accession codes). The long wait is... 

Several human receptors for the neurohypophyseal hormones have been cloned and the sequences elucidated. The human V2 receptor for antidiuretic hormone presumably contains 371 amino acids and seven transmembrane segments and activates cycHc AMP (76). The oxytocin receptor is a classic G-protein-coupled type of receptor with a proposed membrane topography also involving seven transmembrane components (84). A schematic representation of the oxytocin receptor stmcture within the membrane is shown in Eigure 4 (85). 

SKIP produces its effects through two classes of GPCR, SRIF-1 and SRIF-2 that are structurally related to cloned opiate receptors. The agonists,... 

Chen, W.-J., Armour, S., Way, J., Chen, G., Watson, C., Irving, P., Cobb, J., Kadwell, S., Beaumont, K., Rimele, T., and Kenakin, T. P. (1997). Expression cloning and receptor pharmacology of human calcitonin receptors from MCF-7 cells and their relationship to amylin receptors. Mol. Pharmacol. 52 1164-1175. 

Currently, baclofen is the only clinically used GAB Ab receptor agonist. It is used as a muscle relaxant for treatment of spasticity in spinal injury and multiple sclerosis. The cloning of GABAb receptors has renewed the interest in the search for more selective diugs and novel therapeutic indications. 

Y2 receptors were originally cloned from human SMS-KAN cells. Later cloning studies in rats demonstrated that the cloned Y2 receptor is also the molecular correlate of a previously proposed PYY-preferring receptor in the gastrointestinal tract. Messenger RNA for the Y2 receptor has been detected in various parts of the CNS, whereas only low levels of Y2 mRNA were found in human peripheral tissues. 

Zorgato, F., Fugii, J., Otsu, K., et al. (1990). Molecular cloning of encoding cDNA human and rabbit forms of Ca " release channel (ryanodine receptor) of skeletal muscle sarcoplasmic reticulum. J. Biol. Chem. 265, 2244-2256. 

Restivo VA Jr, Lombard LA. Gray GS. Nadler LM Cloning of B7-2 a CTLA-4 counter-receptor that 79 costimulates human T cell proliferation. Science 1993 262 909-911. 

Moss ML, Jin SL, MiUa ME et al (1997) Cloning of a disintegrin metalloproteinase that processes precursor tumour-necrosis factor-alpha. Nature 385 733-736 Nixon RA, Cataldo AM (2006) Lysosomal system pathways genes to neurodegeneration in Alzheimer s disease. J Alzheimers Dis 9 277-289 Noorbakhsh F, VergnoUe N, HoUenberg MD et al (2003) Proteinase-activated receptors in the nervous system. Nat Rev Neurosci 4 981-990... 

Feng Y, Broder CC, Kennedy PE, Berger EA (1996) HIV-1 entry cofactor functional cDNA cloning of a seven-transmembrane, G protein-coupled receptor. Science 272 872-877 Fernandez EJ, LoUs E (2002) Structure, function, and inhibition of chemokines. Annu Rev Pharmacol Toxicol 42 469-499... 

Harrison JK, Barber CM, Lynch KR (1994) cDNA cloning of a G-protein-coupled receptor expressed in rat spinal cord and brain related to chemokine receptors. Neurosci Lett 169 85-89 Harrison JK, Jiang Y, Chen S et al (1998) Role for neuronally derived fractalkine in mediating interactions between neurons and CX3CR1-expressing microglia. Proc Natl Acad Sci USA 95 10896-10901... 

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