Activation by Agonists

Similarly, both a2-adrenergic receptor (Wilson et al, 1990) and the jS2AR (Swaminath and Kobilka, unpublished data) are capable of binding ligands after proteolytic cleavage of loop structures. 

So what do CAMs tell us about GPGR activation We have seen how active states can be achieved by destabilizing the normal arrangement of TM domains by mutations at several different sites. As discussed above, TM domains are held in the basal state primarily by a network of noncovalent interactions between side chains. Thus, any compound that disrupts one of the many intramolecular interactions that stabilize the basal state could have, in principle, agonist activity. The process of disrupting a stabilizing 

Gaborik etal., 2003 Kim etal, 1997 Rasmussen etal., 1999 Scheer etal., 1996) studies. This ionic lock is key in the structure of the receptor, probably in combination with other inter- and/or intrahelical interactions, as it keeps TM6 in a relatively distorted conformation with a marked decrease of the helical twist at the level of the proline kink at Pro2886 50. As a result, the cytoplasmic end of TM6 is much closer to TM3 than would be expected from the distortion induced solely by the proline. 

The P 2AR as a Model System for Ligand Binding and Activation Biophysical Analysis of Agonist-Induced Conformational Changes 

Aspll33 32 in TM3 (Strader et al, 1989a), the catechol hydroxyls interact with serines in TM5 (Liapakis et al, 2000 Strader et al., 1989b Wieland et al, 1996). Interactions with the aromatic ring and the chiral /Mrydroxyl both have been mapped to TM6 (Wieland et al, 1996). 

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Protein kinase C (PKC) is an enzyme family whose members are activated by agonists that cause receptor-mediated generation of lipid second messengers. The activated enzymes transduce information from such agonists by phosphorylating relevant downstream substrates. 

This area has been covered in a review by Eldefrawi and Eldefrawi [23]. The GABA -receptor channel is activated by GABA (Fig. 2), avermectin, muscimol, taurine (Fig. 2) and j -alanine (Fig. 2). The activation by agonists is potentiated by benzodiazepines and barbiturates. The channel is blocked by the competitive... 

Bissantz C. Conformational changes of G protein-coupled receptors during their activation by agonist binding. I Recept Signal Transduct Res 2003 23(2-3) 123-153. 

It is known that protein kinase C can phosphorylate a number of key oxidase components, such as the two cytochrome b subunits and the 47-kDa cytoplasmic factor. This process is prevented by protein kinase C inhibitors such as staurosporine (although it is now recognised that this inhibitor is not specific for protein kinase C), which also inhibits the respiratory burst activated by agonists such as PMA. However, when cells are stimulated by fMet-Leu-Phe, translocation of pAl-phox to the plasma membrane can occur even if protein kinase C activity is blocked - that is, phosphorylation is not essential for the translocation of this component in response to stimulation by this agonist. Similarly, the kinetics of phosphorylation of the cytochrome subunits do not follow the kinetics of oxidase activation, and protein kinase C inhibitors have no effect on oxidase activity elicited by some agonists -for example, on the initiation of the respiratory burst elicited by agonists such as fMet-Leu-Phe (Fig. 6.14). Furthermore, the kinetics of DAG accumulation do not always follow those of oxidase activity. Hence, whilst protein kinase C is undoubtedly involved in oxidase activation by some agonists, oxidase function is not totally dependent upon the activity of this kinase. 

Wang CD, Buck MA, Fraser CM (1991) Site-directed mutagenesis of a2A-adrenergic receptors identification of amino acids involved in iigand binding and receptor activation by agonists. Mol Pharmacol 40,168-179... 

Swaminath, G., Deupi, X., Lee, T. W., Zhu, W., Thian, F. S., Kobilka, T. S., and Kobilka, B. K. (2005). Probing the / 2-adrenoceptor binding site with catechol reveals differences in binding and activation by agonists and partial agonists. / Biol. Chem. 280, 22165-22171. 

PKG and PKA are serine/threonine kinases which become activated by agonists that evoke an increase in either cGMP levels or cAMP levels, respectively. Butt et al. (2000) recently reported that activation of PKG and PKA induced serine phosphorylation of eNOS rendering the enzyme Ca " -independent [39]. In this study eNOS was found to be phosphorylated on serine 1177, serine 633 and threonine 495 allowing for enzyme activation in the absence of calcium-calmodulin. Moreover as there are reports that PKA can activate Akt/PKB via a PI3-kinase dependent pathway [43], various intracellular kinase cascades may interact with one another leading to the control of eNOS activity via phosphorylation. 

Graded dose-response curves also provide information about antagonists—drugs that interact with receptors to interfere with their activation by agonists. 

Several components of the innate immune system must be activated by agonists such as PAMPs, but this activation can occur within minutes or hours rather than days. Therefore, innate reponses are quicker, but the immunity they afford may not be as effective over as long a period of time as adaptive immunity. Nevertheless, the innate immune system represents the all-important first line of defence against pathogens and is absolutely essential for keeping an infection in check before adaptive immunity can be induced. If innate immunity is malignly attacked, the battle against infections is lost from the start. 

These arc eliemicals whose intracellular concentration increases or. more rarely, decrease.s in response to receptor activation by agonists, and which trigger processes that eventually resull in a cellular response. 

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