Agonist-specific coupling

Carreira, M. C., Camina, J. P., Smith, R. G. and Casanueva, F. F., 2004, Agonist-specific coupling of growth hormone secretagogue receptor type la to different intracellular signaling systems. Role of adenosine, Neuroendocrinology, 79, pp 13-25. 

Robb S, Cheek TR, Hannan FL, Hall LM, Midgley JM, Evans PD. Agonist-specific coupling of a cloned Drosophila octopamine/tyramine receptor to multiple second messenger systems. EMBO J 1994 13 1325-1330. 

An example of agonist-specific coupling is shown in Figure 8.3. The receptor in question is the -adrenergic receptor. This receptor triggers at least two different intracellular signaling pathways Arachidonic acid is released by phospholipase A2, and inositoltriphosphate (IP3) is released by phospholipase C. These two effects are mediated by two different G proteins that couple to the same receptor. If we compare the two parameters, the three compounds norepinephrine and meta- and para-octopamine yield substantially different potencies and efficacies. If we hadn t been told otherwise, we would interpret this observation as evidence of two different receptors. In a sense, of course, different GPCR-G protein complexes are different receptors. 

Richardson J, Chatwin H, Hirasawa A, Tsujimoto G, Evans PD. Agonist-specific coupling of a cloned human a, A-adrenoceptor to different second messenger pathways. Naunyn-Schmiedebergs Arch Pharmacol 2003 367 333-341. 

Rudling JE, Richardson J, Evans PD. A comparison of agonist-specific coupling of cloned human a2-adrenoceptor subtypes. Br J Pharmacol 2000 131 933-941. 

De Lean, A., Stadel, J. M., and Lefkowitz, R. J. (1980). A ternary complex model explains the agonist-specific binding properties of the adenylate cyclase-coupled beta-adrenergic receptor./. Biol. Chem. 255, 7108-7117. 

The ability of receptors to couple to G-proteins and initiate GTPase activity may also be independent of ligand. Thus, specific mutations in a- and P-adrenergic receptors have led to receptors that mediate agonist-independent activation of adenylyl cyclase (69,70). These mutations presumably mimic the conformational state of the ligand-activated receptor when they are activated conventionally by ligands. 

Heterologous desensitisation refers to the desensitisation of the response to one agonist by the application of a different agonist. For example, desensitisation of a response to adrenaline by application of 5-HT is mediated by protein kinase A or protein kinase C because these kinases can phosphorylate receptors which are not occupied by agonist. Phosphorylation disrupts the receptor-G-protein interaction and induces the binding of specific proteins, arrestins which enhance receptors internalisation via clathrin-coated pits. Thus desensitisation of G-protein-coupled receptors results in a decrease in the number of functional receptors on the cell surface. 

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