Recent advances in drug action and therapeutics: relevance of novel concepts in G-protein-coupled receptor and signal transduction pharmacology - PubMed (original) (raw)

Review

Recent advances in drug action and therapeutics: relevance of novel concepts in G-protein-coupled receptor and signal transduction pharmacology

C B Brink et al. Br J Clin Pharmacol. 2004 Apr.

Abstract

Problem statement: During especially the past two decades many discoveries in biological sciences, and in particular at the molecular and genetic level, have greatly impacted on our knowledge and understanding of drug action and have helped to develop new drugs and therapeutic strategies. Furthermore, many exciting new drugs acting via novel pharmacological mechanisms are expected to be in clinical use in the not too distant future.

Scope and contents of review: In this educational review, these concepts are explained and their relevance illustrated by examples of drugs used commonly in the clinical setting, with special reference to the pharmacology of G-protein-coupled receptors. The review also addresses the basic theoretical concepts of full and partial agonism, neutral antagonism, inverse agonism and protean and ligand-selective agonism, and the relevance of these concepts in current rational drug therapy. Moreover, the mechanisms whereby receptor signalling (and eventually response to drugs) is fine-tuned, such as receptor promiscuity, agonist-directed trafficking of receptor signalling, receptor trafficking, receptor 'cross-talk' and regulators of G-protein signalling (RGSs) are discussed, from theory to proposed therapeutic implications.

Conclusions: It is concluded that the understanding of molecular receptor and signal transduction pharmacology enables clinicians to improve their effective implementation of current and future pharmacotherapy, ultimately enhancing the quality of life of their patients.

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Figures

Figure 1

A schematic representation of the G-protein ‘activation/deactivation cycle’, associated with the signalling mechanism of G-protein-coupled receptors (GPCRs). Heterotrimeric G-proteins consist of α- and βγ-subunits. Assume a case of no significant constitutive receptor activity. (A) In the resting (inactive) state the GPCR is not coupled to the G-protein. (B) As the agonist binds to the receptor, the equilibrium between the R and R* states is disturbed, so that a larger fraction of the GPCRs is in the R* conformation. The R* conformation couples efficiently with the G-protein, leading to the exchange of GDP for GTP on the Gα-subunit. (C) The Gβγ-subunit is released and both Gα and Gβγ interact with their respective effectors to continue the transduction of the signal. (D) After hydrolysis of GTP to GDP on the Gα-subunit (under influence of GTPase plus RGS) the Gα and Gβγ-subunits reunite. The system returns to its original state as presented in (A) and is ready for the next GPCR-mediated activation. PLC = phospholipase C; AC = adenylyl cyclase; GPCR = G-protein-coupled receptor; GDP = guanosine diphosphate; GTP = guanosine triphosphate

Figure 2

A schematic representation of the two-state receptor model. R, R*, DR and DR* are in constant equilibrium, where D is the drug, R is the receptor in the inactive state, R* is the receptor in the active state, and DR and DR* are the respective drug-receptor complexes (drug-bound receptor). _K_D, _K_D*, L and L (D) are kinetic constants describing the equilibrium between the respective states. In particular, _K_D and _K_D* describe the affinity (binding power) of the drug for the receptor in its inactive and active states, respectively

Figure 3

A schematic representation of how the two-state receptor model relates to the action of drugs as strong agonists, partial agonists, neutral competitive antagonists, inverse agonists, and inverse partial agonists. The inactive and active receptor conformations (R and R*, respectively) are in constant equilibrium. A strong agonist binds selectively to R*, driving the equilibrium between R and R* in favour of R*, resulting in enhanced response. A partial agonist has higher affinity for R* than for R, but with less selectivity than the strong agonist. The neutral competitive antagonist binds with equal affinity to both R and R*, so that it does not disturb the resting equilibrium and therefore does not alter basal response. An inverse strong agonist binds selectively to R, driving the equilibrium between R and R* in favour of R, resulting in decreased response, that is, when there is significant constitutive activity (basal response). An inverse partial agonist has higher affinity for R than for R*, but with less selectivity than the strong inverse agonist

Figure 4

A schematic representation of how receptor promiscuity may lead to either the divergence of one signal transduction pathway into several downstream pathways or the convergence of signal transduction pathways into one pathway. (A) Rx, represents a single GPCR type that couples to two different G protein types G1 and G2, thereby diverging the signal into two independent signal transduction pathways. (B) R1 and R2 are two different GPCR types that both couple to a particular G protein type Gx, so that their signals converge into one signal transduction pathway

Figure 5

A schematic representation of receptor cross-talk, illustrating various examples of GPCR signal transduction pathways, where β2-AR = β2-adrenergic receptor; α2-AR = α2-adrenergic receptor; 5HT2-R = serotonin type 2 receptor; NMDA-R = N-methyl-

-aspartate receptor; ER = endoplasmic reticulum; AC = adenylyl cyclase; PLC = phospholipase Cβ; PDE = phosphodiesterase; PKC = protein kinase C; ATP/GTP = adenosine/guanosine triphosphate; cAMP/cGMP = cyclic adenosine/guanosine monophosphate; PIP2 = phosphatidyl inositol biphosphate; IP3/IP4 = inositol tri/tetra-phosphate; NO = nitric oxide; NOS = nitric oxide synthase; ! = stimulating effect; @ = inhibitory effect

Figure 6

A schematic representation of how the three-state receptor model for GPCRs explains the phenomenon of agonist-directed trafficking of receptor signalling (ADTRS). R is the inactive receptor state, R* the active receptor state coupling to and activating G-protein type 1 (G1) and R** is a second active receptor state coupling to and activating G-protein type 2 (G2). R, R* and R** are in constant equilibrium. Agonists that binds equally well to R* and R** will not display ADTRS, whereas agonists with selective binding to either R* or R** will favour coupling of the GPCR to either G1 or G2, respectively, thereby selectively activating one signal transduction pathway and therefore displaying ADTRS

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Recent advances in drug action and therapeutics: relevance of novel concepts in G-protein-coupled receptor and signal transduction pharmacology - PubMed (original) (raw)