Receptor states

The most probable mechanism for inverse agonism is the same one operable for positive agonism namely, selective receptor state affinity. However, unlike agonists that have a selectively higher affinity for the receptor active state (to induce G-protein activation and subsequent physiological response) inverse agonists have a selectively higher affinity for the inactive receptor state and thus uncouple already spontaneously coupled [RaG] species in the system. 

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... 

To describe this model quantitatively, it is simplest to arbitrarily begin with one receptor state (referred to as [R0]) and define the affinity of a ligand [A] and a G-protein [G] for that state as... 

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

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. 

A few seconds after the addition of the inhibitor, cell responses begin to decay (see Figure 8, Omann and Sklar, this volume). Six cell responses have been characterized in this manner (2i). Because the slowly dissociating receptor state (Figure 2) is found on cells at a time when cell responses have ceased, we suggested that this state was inactive the rapidly dissociating state could be associated with cell activation. 

Which Receptor States Contribute to Cell Activation Of the three states, LRG appears and breaks up during transduction and LRX forms after cell activation. The role of LR is less clear. Conceptually, an LR state in cells can be viewed either as a remnant of the ternary complex which dissociates during transduction... 

Williams DB, Akabas MH. 2002. Structural evidence that propofol stabilizes different GABAa receptor states at... 

Calculate the tunneling probability of an electron and proton through a parabolic barrier of height 1 eV and width of 20 A. Assume particle = 1/2 barrier height and that a receptor state is available for the tunneling particle. (Sidik)... 

One example of this possible existence of a hierarchy of receptor states has been discussed by Frauenfelder (1988). He reviewed studies on the binding of substrates and ligands to myoglobin. The process follows a power law, characterizing the protein as a complex system. Nuclear magnetic resonance (NMR) analyses revealed a number of conformational substates. 

Rm did not correlate with the intrinsic activity of agonists for their ability to attenuate adenylate cyclase stimulation (36).In that system, only the ratio of K./K appeared to correlate with the intrinsic activity ofLthe alpha-adrenergic agonists. Here, in anterior pituitary membranes constant proportions of both receptor states were evidenced but ratios of 30-200 were found for K./Km for a series of dopaminergic agonists despite the fact that these agonists all appear to display full intrinsic activity in their ability to inhibit prolactin secretion from pituitary cells. 

Gay EA, Urban JD, Nichols DE, Oxford GS, Mailman RB. Functional selectivity of D-2 receptor ligands in a Chinese hamster ovary hD(2L) cell line evidence for induction of ligand-specific receptor states. Mol Pharmacol 2004 66 97-105. 

Having examined the leading interpretations of the quantum formalism, a more general theory of atomic structure, consistent with all points of view, could conceivably now be recognized. The first aspect, never emphasized in chemical theory, but fundamental to matrix mechanics, is that the observed frequencies that determine the stationary energy states of an atom, always depend on two states and not on individual electronic orbits. The same conclusion is reached in wave mechanics, without assumption. It means that an electronic transition within atoms requires the interaction between emitter and receptor states and the frequency condition AE(An) = hu, for all pairs in n. This condition by itself offers no rationale for the occurrence of the... 

Ability of the complex to react with complement Ability of the complex to react with cellular receptors State of the mononuclear phagocytic system... 

All receptors are coupled to at least two transducing enzyme systems, phospholipase C and adenylate cyclase. The traditional model of transducing enzyme activation is based upon receptor activation of adenylate cyclase (see Birnbaumer, Chapter 1). In this model the dissociation of the G-protein from its receptor induces a lower-affinity receptor state and facilitates the interaction of the freed G-protein with the catalytic unit of adenylate cyclase, producing either a stimulation... 

---