ksfree.net 3 SECTION 1    G PConstitutively active receptors mebooksfree.net ▼ GPCRs may be constitutively (i.e. spontaneously) active in the absence of any agonist (see Ch. 2 and review by Costa & Cotecchia, 2005). This was first shown for δ opioid receptors (see Ch. 43). There are now many other examples of native GPCRs that show constitutive activity when studied in vitro. The histamine H3 receptor also shows constitutive activity in vivo, and this may prove to be a quite general phenomenon. It means that inverse agonists (see Ch. 2), which suppress this basal activity, may exert effects distinct from those of neutral antagonists, which block agonist effects without affecting basal activity. Agonist specificity mebooksfree.net ▼ It was thought that the linkage of a particular GPCR to a particular signal transduction pathway depends mainly on the structure of the receptor, which confers specificity for a particular G protein, from which the rest of the signal transduction pathway follows. This would imply, in line with the two-state model discussed in Chapter 2, that all agonists acting on a particular receptor stabilise the same activated (R*) state and should activate the same signal transduction pathway, and produce the same type of cellular response. It is now clear that this is an oversimplification. In many cases, for example, with agonists acting on angiotensin receptors, or with inverse agonists on β adrenoceptors, the cellular effects are qualitatively different with different ligands, implying the existence of more than one – probably many – R* states (sometimes referred to as biased agonism; see Ch. 2). Binding of arrestins to GPCRs initiates MAP kinase signalling, such that agonists that induce GRK/arrestin ‘desensitisation’ will terminate some GPCR signalling but may also activate signalling through arrestins that may continue even after the receptor/arrestin complex has been internalised (see Fig. 3.15). Biased agonism has profound implications – indeed heretical to many pharmacologists, who are accustomed to thinking of agonists in terms of their affinity and efficacy, and nothing else; it has added a new dimension to the way in which we think about drug efficacy and specificity (see Kenakin and Christopoulos, 2013). Receptor activity-modifying proteins mebooksfree.net ▼ Receptor activity-modifying proteins (RAMPs) are a family of membrane proteins that associate with some GPCRs and alter their functional characteristics. They were discovered in 1998 when it was found that the functionally active receptor for the neuropeptide calcitonin gene-related peptide (CGRP) (see Chs 16 and 19) consisted of a complex of a GPCR – called calcitonin receptor-like receptor (CRLR) – that by itself lacked activity, with another membrane protein (RAMP1). More surprisingly, CRLR when coupled with another RAMP (RAMP2) showed a quite different pharmacology, being activated by an unrelated peptide, adrenomedulin. In other words, the agonist specificity is conferred by the associated RAMP as well as by the GPCR itself. More RAMPs have emerged, and so far nearly all the examples involve Class B peptide receptors (see Table 3.2), the calcium-sensing receptor being an exception. RAMPs are an example of how protein–protein interactions influence the pharmacological behaviour of the receptors in a highly selective way and may be novel targets for drug development (Sexton et al., 2012). G protein–independent signalling mebooksfree.net ▼ In using the term G protein–coupled receptor to describe the class of receptors characterised by their heptahelical structure, we are following conventional textbook dogma but neglecting the fact that G proteins are not the only link between GPCRs and the various effector systems that they regulate. In this context, signalling mediated through arrestins bound to the receptor (see p. 36), rather than through G proteins, is important (see reviews by Pierce & Lefkowitz, 2001; Delcourt et al., 2007). Arrestins can act as an intermediary for GPCR activation of the MAP kinase cascade (see Fig. 3.15B). There are many examples where the various ‘adapter proteins’ that link receptors of the tyrosine kinase type to their effectors (see p. 42) can also interact with GPCRs (see Brzostowski & Kimmel, 2001), 40 allowing the same effector systems to be regulated by receptors of either type. In summary, the simple dogma that has underpinned much of our understanding of GPCRs, namely, one GPCR gene – one GPCR protein – one functional GPCR – one G protein – one response, is showing distinct signs of wear. In particular: • one gene, through alternative splicing, RNA editing, etc., can give rise to more than one receptor protein; • one GPCR protein can associate with others, or with other proteins such as RAMPs, to produce more than one type of functional receptor; • different agonists may affect a receptor in different ways and elicit qualitatively different responses; • the signal transduction pathway from ‘GPCR’ does not invariably require G proteins, and there can be cross-talk with tyrosine kinase-linked receptors. GPCRs are evidently versatile and adventurous molecules around which much modern pharmacology revolves, and nobody imagines that we have reached the end of the story. discusss gpcr in detail ,give answer for 20 marks, answer should have all imp. details from the picture ,also genertae gpcr diagram, in a pu pharm exam style

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