Receptor signaling agonist

The first case to consider is where the modulator affects only the affinity of the receptor for the agonist but does not alter receptor signaling. Under these circumstances, ,= 1 and Equation 7.3 reduces to... 

The receptor can bind both the probe (agonist, radioligand, [A]) and allosteric modulator ([B]). The agonist (7.11) bound receptor signal through the normal operational model ([AR] complex interacting with cellular stimulus-response machinery with association constant Ke) and in a possibly different manner when the allosteric modulator is bound (complex [ABR] interacting with cell with... 

Used to estimate system independent potency of an allosteric modulator that affects the affinity of the agonist for the receptor but does not affect receptor signaling capability. 

FIGURE 10.19 Patterns of insurmountable blockade of receptors under conditions of (a) hemi-equilibria and (b) allosteric modulation by a modulator that only partially reduces receptor signaling, (a) Concentration-response curves to the full agonist are shifted to the right in a concentration-dependent manner. The maximal response is partially depressed and may attain a plateau level, (b) Curves are shifted to a limiting value characteristic of saturable allosteric modulation. In addition, the maximal response is depressed to a new asymptote. Note that the maximal response is not blocked to basal levels indicative of >0 (see Section 7.8.2 and Equation 7.3). 

In all cases, the molar concentration at which blockade of an agonist response is first encountered is a reasonable indication of the molecular potency of the antagonist, with the possible exception being allosteric modulators that block receptor signaling but increase the affinity of the receptor for the agonist. 

It can be seen from this example that the inhibition curve shifts to the left with increasing concentration of agonist, indicating an allosteric mechanism whereby the modulator blocks receptor signaling but increases the affinity of the receptor for the agonist. 

Natural or synthethic receptor ligands that induce a conformational change (active conformation) and a signal transduction process upon receptor binding. Agonists may act as typical hormones or neurotransmitters or they may confer paracrine functions, recognize bacterial, viral or other environmental constituents via activating their dedicated receptors. 

Schiller PW, Weltrowska G, Schmidt R, Berezowska I, Nguyen TM-D, Lemieux C, Chung NN, Carpenter KA, Wilkes BC. Subtleties of structure-agonist versus antagonist relationships of opioid peptides and peptidomi-metics. J Receptor Signal Transduction Res 1999 19 573-588. 

The balance of opposing pro- and anti-platelet forces determines the overall hemostatic response. Successful hemostasis is achieved when assorted signal-transduction systems, mediators, white blood cells, and platelet receptors for agonists and adhesion molecules overcome the local resistance against platelet activation to generate... 

Cohen, D. P., Thaw, C. N., Varma, A., Gershengorn, M. C., and Nussenzveig, D. R. (1997) Human calcitonin receptors exhibit agonist-independent (constitutive) signaling activity. Endocrinology 138, 1400-1405. 

TP receptor signaling has been extensively docnmented in vascnlar smooth mns-cle and platelets, but its characterization in hnman ASM cells has been more limited until recently. ASM cells express messenger RNA (mRNA) for both TP receptor isoforms, and functional receptors respond to agonist with an increase in intracellular Ca " concentration (200). As a consequence, besides potentiating the epidermal growth factor (EGF) mitogenic response independently from transactivation of the EGF receptor (EGER) (200), TP receptor stimulation induces a concentration-dependent increase in DNA synthesis. 

McGraw DW, Almoosa KF, Paul RJ, Kobilka BK, Liggett SB. (2003) Antithetic regulation by beta-adrenergic receptors of Gq receptor signaling via phospholipase C underlies the airway beta-agonist paradox. J Clin Invest. 112, 619-626. 

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