Constitutive activated receptor

In constitutively active receptor systems (where the baseline is elevated due to spontaneous formation of receptor active states, see Chapter 3 for full discussion), unless the antagonist has identical affinities for the inactive receptor state, the spontaneously formed active state, and the spontaneously G-protein coupled state (three different receptor conformations, see discussion in Chapter 1 on receptor conformation) it will alter the relative concentrations of these species—and in so doing alter the baseline response. If the antagonist has higher affinity for the... 

FIGURE 6.12 Schild analysis for constitutively active receptor systems, (a) Competitive antagonism by the inverse agonist in a constitutively active receptor system with DR values calculated at the EC80. 

Used to estimate system independent potency of an inverse agonist in a constitutively active receptor system. 

X = transducer function for response to the full agonist and constitutively active receptor state. 

FIGURE 1.11 A model to show the influence of a ligand, L, on the equilibrium between the active and inactive forms of a constitutively active receptor, R. Note that if L, R, and LR are in equilibrium, and likewise L, R and LR, then the same must hold for LR and LR (see Appendix 1.6B (Section 1.6.7.2) for further explanation). 

The stndy of activating and inactivating GNASl mutations, therefore, has served to elucidate the tissue-specific regulation of GPCR signaling. G protein subunits and accessory proteins have a great hold over the activity of a mnltitude of receptors. Disruptions to the G a subunit, on one extreme, can resemble phenotypes caused by numerous constitutively active receptor variants, while on the other extreme they can resemble complex phenotypic patterns of tissne-specific receptor inactivation. 

Burk O, Koch I, Raucy J, et al. The induction of cytochrome P450 3A5 (CYP3A5) in the human liver and intestine is mediated by the xenobiotic sensors pregnane X receptor (PXR) and constitutively activated receptor (CAR). J Biol Chem 2004 279(37) 38379-38385. 

Figure 7 shows that, indeed, the relative efficacy of inverse agonists differs markedly depending on the response measured. Note especially the markedly different relative efficacies of SB 242084 and SB 243213. SB 242084 displays a relatively strong inverse agonism toward PLA2, Gai activation, and the PLC sensitization response however, for the basal PLC response, SB 242084 is an agonist (also see Fig. 8). SB 243213 also is a relatively strong inverse agonist for all responses except the basal PLC response, where it is an antagonist. These data support the contention that constitutive activity and inverse agonist relative efficacy are response dependent and that the receptor stimulus from constitutively active receptors is also different for different responses.

Theoretically, inverse agonists may be useful agents for the treatment of disease symptoms caused by constitutive receptor activity. Covalent modifications of the receptor protein, pathological increase in receptor or G protein densities, or inherited or somatic point mutations may lead to increased constitutive receptor activity. For example, certain inherited point mutations in rhodopsin have been shown to cause retinitis pigmentosa. The involvement of inherited, constitutively activating receptor point mutations has also been demonstrated in certain forms of hyperthyroidism, in male precocious puberty, and in Jansen-type metaphyseal chondrodysplasia [8]. Constitutive G protein activity may also be an important factor in autoimmune diseases [9]. 

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