Receptor isomerization

Receptor isomerization to the active form occurs when the binding site is occupied by A but not by the antagonist B ... 

Scheer, A., Costa, T., Fanelli, F., et al. (2000) Mutational analysis of the highly conserved arginine within the Glu/Asp-Arg-Tyr motif of the alpha) lb)-adrenergic receptor effects on receptor isomerization and activation. Mol. Pharmacol. 57,219-231. 

Under these circumstances, the observed affinity of the ligand for the receptor will not be described by Ka (where KA=1/Ka) but rather by that microaffinity modified by a term describing the avidity of the isomerization reaction. The observed affinity will be given by (see Section 4.6.7)... 

Vitamin D3 (VD3) and retinoids synergistically inhibit the growth and progression of squamous cell carcinomas and actinic keratoses in chronically sun exposed skin. One reason for this synergism may be the direct influence of VD3 on the isomerization and the metabolism of RA. Here, VD3 inhibits the isomerization of 13-cis-RA to the more receptor active all-trans and 9-cis-isomers. Moreover, the VD3 derivative secocholestra-trien-l,3,24-triol (tacalcitol), used for the treatment of severe keratinizing disorders inhibits 4-hydroxylation of all-ri ans-RA. 

During the 1940s, more than 15 years before the structure of (67) was elucidated as the major psychoactive constituent of marijuana [90] and 40 years before the identification of specific cannabinoid receptors, Adams and co-workers [91, 92] demonstrated that a T,2 -dimethylheptyl (T,2 -DMH) side chain was the optimal 3-alkyl substituent for carmabinoid activity in vivo in the A ° -THC series. In this early research, the ataxia test in dogs was used as a standard measure of psychoactive cannabinoid activity. The isomeric l, l -DMH side chain was found to be less potent than the l, 2 -DMH one in the series, but the two side chains have similar... 

When the natural product source contains racemic mixtures (of isomeric forms), then clearly the assignment of signal value to either or both variants of a compound needs to be determined. Alterations in receptor detection of chirality can change sensitivity to the geometrically alternate compound over the range 101 to 106. Of the lactones passed into urine and deposited on tarsal hairs of Black-tailed deer (Odocoileus... 

This approximates to unity if [A] is either very large or very small. In between, H may be as much as 2 for very large values of E. It is noteworthy that this should be so even though the affinities for the first and the second binding steps have been assumed to be the same, provided only that some isomerization of the receptor to the active form occurs. This is because isomerization increases the total amount of binding by displacing the equilibria shown in Eq. (1.9) to the right — that is, toward the bound forms of the receptor. 

Just a year after Stephenson s classical paper of 1956, J. del Castillo and B. Katz published an electrophysiological study of the interactions that occurred when pairs of agonists with related structures were applied simultaneously to the nicotinic receptors at the endplate region of skeletal muscle. Their findings could be best explained in terms of a model for receptor activation that has already been briefly introduced in Section 1.2.3 (see particularly Eq. (1.7)). In this scheme, the occupied receptor can isomerize between an active and an inactive state. This is very different from the classical model of Hill, Clark, and Gaddum in which no clear distinction was made between the occupation and activation of a receptor by an agonist. 

A difficulty encountered in such work, and one that has to be considered in any study of the relationship between the concentration of an agonist and its action, is the occurrence of desensitization. The response declines despite the continued presence of the agonist. Several factors can contribute. One that has been identified in work with ligand-gated ion channels is that receptors occupied by agonist and in the active state (AR ) may isomerize to an inactive, desensitized, state, ARd. This can be represented as ... 

Here, the agonist-receptor complex (AR) combines with a G-protein (G) to form a ternary complex (ARG ), which can initiate further cellular events, such as the activation of adenylate cyclase. However, this simple scheme (the ternary complex model) was not in keeping with what was already known about the importance of isomerization in receptor activation (see Sections 1.2.3 and 1.4.3), and it also failed to account for findings that were soon to come from studies of mutated receptors. In all current models of G-protein-coupled receptors, receptor activation by isomerization is assumed to occur so that the model becomes ... 

The law of mass action was first applied to competitive antagonism by Clark, Gaddum, and Schild at a time before the importance of receptor activation by isomerization was established. It was assumed, therefore, that the equilibrium among agonist, antagonist, and their common binding site could be represented quite simply by the reactions ... 

Based on these rather extensive and not entirely realistic assumptions, the fraction of the receptors in the AR state is given by Eq. (1.32) however, only some of these agonist-combined, isomerized, receptor macromolecules are free of antagonist and thus able to initiate a response. To... 

D. For this simulation the equilibrium constant for isomerization between AR and the AR has been set so that few of the receptors are in the active state even in the presence of a large concentration of A on its own. However, with B also present at increasing concentrations, the equilibria shown in Figure 1.28 are shifted toward the active forms so that the maximum response to A rises to a point at which almost all of the receptors can be activated. In effect, B is acting as a co-agonist. Note that it causes little receptor activation when [A] is small. 

We see from this that the value of the fourth equilibrium constant (for isomerization between the active and inactive forms of the occupied receptor) is determined by the other three, E0, KL, and K] ... 

K KJa 2. a is the factor by which the affinity of the active form (R ) for A exceeds that of R. It also expresses the increase in the tendency for the receptor to isomerize to the active form when the binding site for A alone is occupied. 

What quantity would Furchgott s irreversible antagonist method (Section 1.6.4) estimate if the occupied receptor, AR, must first isomerize to a second form, AR, which then attaches to another entity, such as a G-protein, in order to elicit a response (as in Eq. (1.38)) Assume that the G-protein is present in great excess in relation to the receptors. 

In the case of multiple binding sites or if the ligand-receptor complex isomerizes, the onset and offset curves will be multiexponential. It is generally assumed that nonspecific binding will occur rapidly, and this should certainly be so for simple entrapment in a membrane or cell pellet. If, however, specific binding is very rapid or nonspecific binding particularly slow (possibly... 

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