Cascade receptors

Figure 5.2 Schematic diagram of the three different types of simultaneous ion pair receptors, (a) cascade receptor, (b) ditopic receptor and (c) zwitterion receptor.

A cascade receptor is a host that binds one of more metal ions which, in turn, bind anions. They are of interest in the modelling of biological metal-based active sites — metallobiosites. 

Cascade receptors represent the earliest simultaneous receptors and some examples date back to the 1970s and 1980s. Typically, more than one metal ion (cation) coordinates to a particular ligand (often a Schiff base or macrocyclic heteroalkane) in a well-defined geometry and the anionic species then coordinates to the metal centre (Figure 2.21(a)) - this complex is known as a casacade... 

Cascade receptors are those in which the distance between the two binding functionalities is so short as to allow cooperative contact ion-pair binding. These receptors first bind one of the ions, often it happens to be the cation, which becomes the new binding site for the counterion, showing a higher affinity because of maximized coulombic attraction. 

Fig. 20. (a) Schematic illustration of the formation of a cascade complex (b) a heterodinuclear cation complex of a diloop crown receptor and (c) a typical... 

These cascades serve as operational amplifiers of the initial ligand—receptor interaction. In each step of the process, amplification by several powers of 10 may occur so that an original signal maybe multiphed several millionfold (63). 

The G-proteins are heterotrimers made of three families of subunits, a, P, and y, which can interact specifically with discrete regions on G-protein-coupled receptors. This includes most receptors for neurotransmitters and polypeptide hormones (see Neuroregulators). G-protein-coupled receptors also embrace the odorant receptor family and the rhodopsin-linked visual cascade. 

A critical component of the G-protein effector cascade is the hydrolysis of GTP by the activated a-subunit (GTPase). This provides not only a component of the amplification process of the G-protein cascade (63) but also serves to provide further measures of dmg efficacy. Additionally, the scheme of Figure 10 indicates that the coupling process also depends on the stoichiometry of receptors and G-proteins. A reduction in receptor number should diminish the efficacy of coupling and thus reduce dmg efficacy. This is seen in Figure 11, which indicates that the abiUty of the muscarinic dmg carbachol [51 -83-2] to inhibit cAMP formation and to stimulate inositol triphosphate, IP, formation yields different dose—response curves, and that after receptor removal by irreversible alkylation, carbachol becomes a partial agonist (68). 

The operational model allows simulation of cellular response from receptor activation. In some cases, there may be cooperative effects in the stimulus-response cascades translating activation of receptor to tissue response. This can cause the resulting concentration-response curve to have a Hill coefficient different from unity. In general, there is a standard method for doing this namely, reexpressing the receptor occupancy and/or activation expression (defined by the particular molecular model of receptor function) in terms of the operational model with Hill coefficient not equal to unity. The operational model utilizes the concentration of response-producing receptor as the substrate for a Michaelis-Menten type of reaction, given as... 

There are a number of assay formats available to test drugs in a functional mode. As discussed in Chapter 2, a main theme throughout the various stimulus-response cascades found in cells is the amplification of receptor stimulus occurring as a function of the distance, in biochemical steps and reactions, away from the initial receptor event. Specifically, the further down the stimulus-... 

Hyperbola (hyperbolic), a set of functions defining nonlinear relationships between abscissae and ordinates. This term is used loosely to describe nonlinear relationships between the initial interaction of molecules and receptors and the observed response (i.e., stimulus-response cascades of cells). 

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