Receptor expression

FK-506 (37) interferes with IL-2 synthesis and release and has a cyclosporin-like profile, but is considerably more potent in vitro. IC q values are approximately 100-fold lower. This neutral macroHde suppresses the mixed lymphocyte reaction T-ceU proliferation generation of cytotoxic T-ceUs production of T-ceU derived soluble mediators, such as IL-2, IL-3, and y-IFN and IL-2 receptor expression (83). StmcturaHy, FK-506 is similar to sirolimus. Mycophenolate mofetil (33), brequinar (34), and deoxyspergualin are in various phases of clinical evaluation. Identification of therapeutic efficacy and safety are important factors in the deterrnination of their utiUty as immunosuppressive agents. 

DiaZepin Nucleosides. Four naturally occurring dia2epin nucleosides, coformycin (58), 2 -deoxycoformycin (59), adechlorin or 2 -chloro-2 -deoxycoformycin (60), and adecypenol (61), have been isolated (1—4,174,175). The biosynthesis of (59) and (60) have been reported to proceed from adenosine and C-1 of D-ribose (30,176,177). They are strong inhibitors of adenosine deaminase and AMP deaminase (178). Compound (58) protects adenosine and formycin (12) from deamination by adenosine deaminase. Advanced hairy cell leukemia has shown rapid response to (59) with or without a-or P-interferon treatment (179—187). In addition, (59) affects interleukin-2 production, receptor expression on human T-ceUs, DNA repair synthesis, immunosuppression, natural killer cell activity, and cytokine production (188—194). 

The extended ternary complex model can take into account the phenomenon of constitutive receptor activity. In genetically engineered systems where receptors can be expressed in high density, Costa and Herz [2] noted that high levels of receptor expression uncovered the existence of a population of spontaneously active receptors and that these receptors produce an elevated basal response in the system. The relevant factor is the ratio of receptors and G-proteins (i.e., elevated levels of receptor cannot yield constitutive activity in the absence of adequate amounts of G-protein, and vice versa). Constitutive activity (due to the [RaG] species) in the absence of ligand ([A] = 0) is expressed as... 

Constitutive activity can be produced in a recombinant system by increasing the level of receptors expressed on the cell membrane. The formation of the constitutively active... 

It can be seen from this equation that maximal constitutive activity need not reach a maximal asymptote of unity. Submaximal constitutive activity has been observed with some receptors with maximal receptor expression [28]. While there is scattered evidence that the cubic ternary complex is operative in some receptor systems, and while it is thermodynamically more complete, it also is heuristic... 

FIGURE 3.12 Dependence of constitutive receptor activity as ordinates (expressed as a percent of the maximal response to a full agonist for each receptor) versus magnitude of receptor expression (expressed as the amount of human cDNA used for transient transfection, logarithmic scale) in Xenopus laevis melanophores. Data shown for human chemokine CCR5 receptors (open circles), chemokine CXCR receptors (filled triangles), neuropeptide Y type 1 receptors (filled diamonds), neuropeptide Y type 2 receptors (open squares), and neuropeptide Y type 4 receptors (open inverted triangles). Data recalculated and redrawn from [27],... 

FIGURE 5.4 Microphysiometry responses of HEK 293 cells transfected with human calcitonin receptor, (a) Use of microphysiometry to detect receptor expression. Before transfection with human calcitonin receptor cDNA, HEK cells do not respond to human calcitonin. After transfection, calcitonin produces a metabolic response, thereby indicating successful membrane expression of receptors, (b) Cumulative concentration-response curve to human calcitonin shown in real time. Calcitonin added at the arrows in concentrations of 0.01, 0.1, 1.10, and lOOnM. Dose-response curve for the effects seen in panel B. 

The first idea to consider is the effect of receptor density on sensitivity of a functional system to agonists. Clearly, if quanta of stimulus are delivered to the stimulus-response mechanism of a cell per activated receptor the amount of the total stimulus will be directly proportional to the number of receptors activated. Figure 5.8 shows Gi-protein-mediated responses of melanophores transiently transfected with cDNA for human neuropeptide Y-l receptors. As can be seen from this figure, increasing receptor expression (transfection with increasing concentrations of receptor cDNA) causes an increased potency and maximal response to the neuropeptide Y agonist PYY. 

Constitutive receptor activity, receptors spontaneously produce conformations that activate G-proteins in the absence of agonists. This activity, referred to as constitutive activity, can be observed in systems in which the receptor expression levels are high and the resulting levels of spontaneously activating receptor species produce a visible physiological response. An inverse agonist reverses this constitutivie activity and thus reduces, in a dose-dependent... 

Arg-2, Pro-3, Arg-4, Leu-5, Ser-6, Lys-8 Gly-9, Pro-10 and Met-11 into apelin-13 reduced [125I]-(Pyr1)apelin-13 binding to apelin receptors expressed in cell lines, suggesting they are important residues for receptor interaction. Structure activity studies using fragments of apelin-17 also identified Gln-1, Pro-12 and Phe-13 not essential for apelin binding. 

Proteins embedded in the shell of lipoproteins. They serve as scaffold for assembly of the lipoprotein particle in the endoplasmic reticulum. In addition, they control metabolism of lipoproteins in the circulation by interaction with enzymes such as lipases. Finally, apolipoproteins determine cellular uptake of the particles by interaction with specific lipoprotein receptors expressed on the surface of target cells. 

Although leukocytes continue to be the major site of expression of chemokine receptors, several studies have recently demonstrated chemokine receptor expression on neurons in the CNS. 

Sites of endothelin-receptor expression. ETA receptors are expressed in the smooth muscle cells of the vascular medial layer and the airways, in cardiac myocytes, lung parenchyma, bronchiolar epithelial cells and prostate epithelial cells. ETB receptors are expressed in endothelial cells, in bronchiolar smooth muscle cells, vascular smooth muscle cells of certain vessels (e.g. saphenous vein, internal mammary artety), in the renal proximal and distal tubule, the renal collecting duct and in the cells of the atrioventricular conducting system. 

In addition, ETB receptors are upregulated in vessels with atherosclerotic lesions and in pulmonary vessels of patients with severe pulmonary hypertension. The upregulation can be attributed to increased ETB receptor expression in smooth muscle cells and to ETB receptors expressed on infiltrating macrophages. 

In the vascular system, endothelial ETB receptors mediate a transient vasodilation, whereas ETA receptors cause a long-lasting vasoconstriction. The role of ETb receptors expressed on smooth muscle cells... 

The successful clinical application of RTK-based therapeutics in the last 8 years instigates further research to generate the next generation drugs. Thus, antisense RNAs or dominant-negative receptor mutants are being tested for their ability to reduce receptor expression. 

Interleukin 2 (IL-2) is a 15.5 kDa glycosylated protein produced by helper T-cells in response to an antigen and interleukin-1. Ligation of the IL-2 receptor (expressed by a number of lymphocytes) by IL-2 stimulates growth, differentiation and survival. 

Pattern recognition receptors (PRRs) are receptors expressed by cells from the innate immune system... 

Sensory receptors expressed in particular in taste receptor cells of the taste buds that sense the five basic tastes salt, sour, sweet, bitter and umami (glutamate taste). Sodium type ion channels sense salty taste whereas sour taste is transduced by potassium type ion channels. The underlying cause of sweet, bitter, and umami tastes is the selective activation of different groups of G protein coupled receptors that discriminate between sweet, bitter, and umami tasting molecules. 

Similarly, in developing Drosophila the response to wg is influenced by the relative abundance and ligand affinity of receptors expressed in the target tissue. A synthesis of the available data from all species suggests that the response to a specific Wnt signal in vivo is influenced both by the particular Wnt protein secreted and by the receptors and other downstream molecules present in the target tissue. 

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