Heterogeneity of receptors

Screening the molecular heterogeneity of receptor expression in endothelial cell surfaces is required for the development of vascular-targeted therapies. First, as opposed to targeting purified proteins as discussed above, membrane-bound receptors are more likely to preserve their functional conformation, which can be lost upon purification and immobilization outside the context of intact cells. Moreover, many cell surface receptors require the cell membrane microenvironment to function so that protein-protein interaction may occur. Finally, combinatorial approaches may allow the selection of cell membrane ligands in a functional assay and without any bias about the cellular surface receptor. Therefore, even as yet unidentified receptors may be targeted. 

In addition to inhibition of AC, stimulation of both the o a- and 0C2C-ARs results in direct activation of PLC via a PTX-sensitive G protein (241). Hence, as for many other receptor subtypes, ARs can couple to multiple effector systems, indicating heterogeneity of receptor-effector interactions. In addition, the effector pathway utilized is dependent on the specific ligand employed and its concentration. 

Gutman M, Singh RK, Radinsky R, et al. Intertumoral heterogeneity of receptor-tyrosinase kinase expression in human melanoma cell lines with metastatic capabilities. Anticancer Res. 1994 14 1759-1765. 

Statistical copolymerisation kinetics with the crosslinker lessens the heterogeneity of receptor sites. 

Natural venoms are a vast reservoir of toxins with diverse pharmacological properties and phylogenetic specificities. It seems likely that toxin diversity is an evolutionary response of venomous predators to a dynamic heterogeneity of receptors in prey animals. Toxins are thus valuable tools for distinguishing differences in ion channel targets. The potent effects exerted by toxins on the nervous system has obvious applications for both pest control, drug development, and basic neuroscience. 

It may be safely assumed that each of these sets of receptor locations is structurally somewhat heterogeneous, and that it occupies a specific area of the sensory epithelium, with a characteristic, possibly very complex, topology. Because knowledge of this taste modality is still minimal, the topological structure of the taste modality is pure speculation. One such speculation was offered by Beets. To simplify his reasoning, Beets assumed the topology to refer to a two-dimensional area of the sensory... 

Sieghart, W and Karobath, M (1980) Molecular heterogenity of benzodiazepine receptors. Nature... 

Because the clinical data from these three failed trials have not been reported in any detail, it is hard to determine whether their lack of efficacy is attributable to the bioavailability of the molecules themselves or whether it could be more directly related to the role of the receptors CCR1 and CXCR3 in the pathogenesis of the diseases targeted. More likely, the heterogeneity of autoimmune... 

Dunlap J, Brown JH. Heterogeneity of binding sites on cardiac muscarinic receptors induced by the neuromuscular blocking agents gallamine and pancuronium. Mol Pharmacol 1983 24 15-22. 

Martin, R.J., Robertson, A.P., Bjorn, H. and Sangster, N.C. (1997) Heterogeneous levamisole receptors a single-channels study of nictotinic acetylcholine receptors from Oesophagostomum dentatum. European Journal of Pharmacology 322, 249-257. 

Thus, cholinergic receptor classification can be considered in terms of three stages of development. Initially, Dale [2] distinguished nicotinic and muscarinic receptor subtypes with crude alkaloids. Then, chemical synthesis and structure-activity relationships clearly revealed that nicotinic and muscarinic receptors were heterogeneous, but chemical selectivity could not come close to uncovering the true diversity of receptor subtypes. Lastly, analysis of subtypes came from molecular cloning, making possible the classification of receptors on the basis of primary structure (Fig. 11-2). 

Apart from the heterogeneity of apo(a), caused by a varying number of Lpa-KIV2-kringles and the degree of glycosylation (varying up to 35%) (G26), human Lp(a) seems to exist of two species with different affinities for lysine-Sepharose (L13), but similar interaction with LDL-receptor in vitro (A15). This... 

In some instances, flow cytometry assays are a superior alternative to conventional procedures for the determination of equilibrium binding constants (Stein et al., 2001). In contrast to assays that employ radiolabelled ligands, which measure population mean values for binding constants, flow cytometry methods can measure those values in individual cells, revealing heterogeneity in receptor expression within a population of cells or membrane vesicles. Furthermore, small samples can be characterized in a short period of time (hours). This approach to receptor-binding analysis may be limited only by the availability of a properly characterized fluorescent ligand. 

With respect to a multi-subunit LGIC receptor, a common approach is to inject oocytes with an equivalent molar ratio of each transcript. However, it should be noted that the ratio of injected transcripts might have an effect on the final stoichiometry of subunits in the expressed receptors (e.g., Boileau et aL, 2002). This may lead to an expression of a heterogeneous population of receptors that can complicate functional analysis. 

---