Two Receptor Model

P42/44 wttalMd PTK aclKniion nd tramtocation prothrembinaM attaoibV C pool-1 I 

FIGURE 3 The two receptor model of thrombin-induced platelet activation. See text for details. Modified from, with permission. 

3 protein) can be co-immunoprecipitated with GPIb but the role of tiiis interaction in the effects of a-thrombin on platelets, as conq ared with those of vWF, remains to be elucidated. However, the TLP-independent events described earlier, such as the sustained activation of p42/44 and other Idnases and their translocation to the cytoskeleton may be provisionally assigned to this high affinity GPIb-dependent pathway. The Ca pool mobilized by this receptor may be different finm that mobilized by the moderate affinity, PARI-dependent pathway since inununoinhibition reaches a maximum of 50% in each case. 

Taking the two receptor model as a le, it may be noted that those activities ch have been shown to require continuous receptor occupancy, such as arachidonate mobilization and the fonnaticm of dx sphatidic add, are mediated through the high affinity pathway and represent a receptor-hgand mediated mechanism while those receptor activities that require only transient receptor occupancy, such as the synthesis and breakdown of phosphoinositides, correspond to the moderate affinity proteolytic PARI pathway. The feet feat immunoinhibitoty effects at either receptor can be overcome at elevated thrombin levels merely indicates fee relatively high affinities of thrombin binding at both sites ( 0.5nM and lOnM, respectively) as compared with fee relatively low affinities of fee 

In summary, the available evidence strongly siq poits the two receptor model for thrombin-induced platelet activation. In this model a siqrerconyrlexed form of GPIb acts as the high affinity receptor while PARI acts as the moderate affinity receptor. The s plicability of this model in other cell systems, and the relative contributions of the two receptor pathways in the normal or pathophysiological activation of platelets, remain to be determined. 

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Fig. 14 Relationships among dose, incapacitation and lethality in a two-receptor model at equilibrium. (Klotz et al.)...

HUMAN PLATELET THROMBIN RECEPTORS AND THE TWO RECEPTOR MODEL FOR PLATELET ACTIVATION... 

Smith, W.L. and Garcia-Perez, A. (1980). A two-receptor model for the mechanism of action of prostaglandins in the renal collecting tubule. In Bailey, J.M. (ed.) Prostaglandins, Leukotrienes, and Lipoxins, pp. 35-45. (New York and London Plenum Press)... 

Ishibashi S, Herz J, Maeda N, Goldstein JL, Brown MS (1994) The two-receptor model of lipoprotein clearance Tests of the hypothesis in knockout mice lacking the low density lipoprotein receptor, apolipoprotein E, or both proteins. Proc Natl Acad Sci USA 91 4431-4435... 

The form of that function is shown in Figure 3.2. There are two specific parameters that can be immediately observed from this function. The first is that the maximal asymptote of the function is given solely by the magnitude of A/B. The second is that the location parameter of the function (where it lies along the input axis) is given by C/B. It can be seen that when [Input] equals C/B the output necessarily will be 0.5. Therefore, whatever the function the midpoint of the curve will lie on a point at Input = C/B. These ideas are useful since they describe two essential behaviors of any dmg-receptor model namely, the maximal response (A/B) and the potency (concentration of input required for effect C/B). Many of the complex equations... 

The extended ternary complex model [23] was conceived after it was clear that receptors could spontaneously activate G-proteins in the absence of agonist. It is an amalgam of the ternary complex model [12] and two-state theory that allows proteins to spontaneously exist in two conformations, each having different properties with respect to other proteins and to ligands. Thus, two receptor species are described [Ra] (active state receptor able to activate G-proteins) and [RJ (inactive state receptors). These coexist according to an allosteric constant (L = [Ra]/[Ri]) ... 

Cubic ternary complex model, a molecular model (J. Their. Biol 178, 151-167, 1996a 178, 169-182, 1996b 181, 381-397, 1996c) describing the coexistence of two receptor states that can interact with both G-proteins and ligands. The receptor/G-protein complexes may or may not produce a physiological response see Chapter 3.11. 

Two-state model, a model of proteins that coexists in two states controlled by an equilibrium constant. Molecules with selective affinity for one of the states will produce a bias in that state upon binding to the system. Two-state theory was conceived to describe the function of ion channels but also has relevance to receptors (see Chapter 3.7). 

In the simple two-state model shown in equation (A3.1) the receptor can only exist in either free or bound states and so... 

Denileukin diftitox is a combination of the active sections of interleukin 2 and diphtheria toxin. It binds to high-affinity interleukin 2 receptors on the cancer cell (and other cells), and the toxin portion of the molecule inhibits protein synthesis to result in cell death. The pharmacokinetics of denileukin diftitox are best described by a two-compartment model, with an a half-life of 2 to 5 minutes and a terminal half-life of 70 to 80 minutes. Denileukin diftitox is used for the treatment of persistent or recurrent cutaneous T-cell lymphoma whose cells express the CD25 receptor. Side effects include vascular leak syndrome, fevers/chills, hypersensitivity reactions, hypotension, anorexia, diarrhea, and nausea and vomiting. 

Rituximab is a monoclonal antibody to the CD20 receptor expressed on the surface of B lymphocytes the presence of the antibody is determined during flow cytometry of the tumor cells. Cell death results from antibody-dependent cellular cytotoxicity. The pharmacokinetics of rituximab are best described by a two-compartment model, with a terminal half-life of 76 hours after the first infusion and a terminal half-life of 205 hours after the fourth dose.36 Rituximab has shown clinical activity in the treatment of B-cell lymphomas that are CD20+. Side effects include hypersensitivity reactions, hypotension, fevers, chills, rash, headache, and mild nausea and vomiting. 

Toremifene is an estrogen receptor antagonist. The pharmacokinetics of toremifene are best described by a two-compartment model, with an a half-life of 4 hours and an elimination half-life of 5 days. Peak plasma concentrations are achieved approximately 3 hours after an oral dose. Toremifene is metabolized extensively, with metabolites found primarily in the feces. Toremifene is used for the treatment of metastatic breast cancer in postmenopausal women with estrogen-receptor-positive or unknown tumors. Toremifene causes hot flashes, vaginal bleeding, thromboembolism, and visual acuity changes. 

In vivo roles of CXCR1 and CXCR2 and their ligands were investigated using rabbits in which the orthologues of IL-8 and its two receptors have been identified. Intravenous injection of a neutralizing anti-IL-8 antibody prevented neutrophil accumulation and activation in a model of reperfusion tissue injury... 

The term state rather than condition is often used in this context. However, the latter seems preferable in an introductory account. This is because the del Castillo-Katz mechanism is often described as a two-state model of receptor action, meaning here that the occupied receptor exists in two distinct (albeit interconvertible) forms, AR and AR, whereas three conditions of the receptor (R, AR, and AR ) have to be identified when applying the law of mass action to the binding of the ligand, A. 

Recently, numerous studies reported the application of homonuclear and heteronuclear selective recoupling schemes on uniformly labelled ligand interacting with membrane receptors. The polarization exchange curves were fitted with the two-spin model and showed that it is possible to determine intemuclear distances up to 4.5 A.118... 

Eisner Your model of how the oscillation is maintained requires that the NCX in the surface membrane be very close to the SERCA in the SR. But presumably you can t have the InsP3 and RyRs in this place, because if they were they would release Ca2+ into the space and this would make it impossible for backwards NCX to bring Ca2+ in. Later on, towards the end of your paper, the SERCA has moved away from the Na+/Ca2+ exchanger and the RyR is close to the Na+/Ca2+ exchange in order that Ca2+ could be pumped out of the cell. Do you require two different models to explain the two different sorts of experiments, and do either of them fit with what is known about the localization of the various receptors ... 

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