Elsevier

Cellular Signalling

Volume 21, Issue 2, February 2009, Pages 179-185
Cellular Signalling

Review
Membrane signalling complexes: Implications for development of functionally selective ligands modulating heptahelical receptor signalling

https://doi.org/10.1016/j.cellsig.2008.08.013Get rights and content

Abstract

Technological development has considerably changed the way in which we evaluate drug efficacy and has led to a conceptual revolution in pharmacological theory. In particular, molecular resolution assays have revealed that heptahelical receptors may adopt multiple active conformations with unique signalling properties. It is therefore becoming widely accepted that ligand ability to stabilize receptor conformations with distinct signalling profiles may allow to direct the stimulus generated by an activated receptor towards a specific signalling pathway. This capacity to induce only a subset of the ensemble of responses regulated by a given receptor has been termed “functional selectivity” (or “stimulus trafficking”), and provides the bases for a highly specific regulation of receptor signalling. Concomitant with these observations, heptahelical receptors have been shown to associate with G proteins and effectors to form multimeric arrays. These complexes are constitutively formed during protein synthesis and are targeted to the cell surface as integral signalling units. Herein we summarize evidence supporting the existence of such constitutive signalling arrays and analyze the possibility that they may constitute viable targets for developing ligands with “functional selectivity”.

Introduction

Heptahelical receptors play an important role in cellular communication, translating a large variety of external stimuli (hormones, neurotransmitters, ions, light) into signals that can be decoded by the cell. The process by which extracellular information is transferred to the cytosolic compartment relies on a series of structural modifications that are imposed on the receptor upon ligand binding and that subsequently trigger a diversity of biochemical changes that influence vital processes within the cell. Production of ligands that influence transmission of information through heptahelical receptors is one of the most commonly used approaches in the production of therapeutic agents and, for more than fifty years, development of such ligands has been guided by the notion that heptahelical receptors behave as bimodal switches which alternate between an active and an inactive conformation [1]. Within this context, efficacy has been considered as the result of drug ability to stabilize different amounts of a single active state of the receptor. However, the advent of recombinant systems has allowed to monitor consequences of receptor activation in an increasingly varied number of readouts, and with this ability came the realization that ligands for a given receptor may display very different efficacy profiles depending on the signalling pathway in which drugs were tested [2], [3], [4], [5], [6]. The observed differences could not be simply attributed to accumulation of a single active state [7] and called for an amendment of the classically accepted theoretical framework so as to incorporate the possibility that heptahelical receptors may adopt multiple active conformations [8], [9]. Within this alternative model it became possible to define a novel pharmacological property characterized by the ability of the ligand to stabilize a receptor conformation which triggers only a subset of responses within the ensemble of events associated with receptor activation [9]. This property termed “functional selectivity” (or “stimulus trafficking” or “biased agonism”) [7], [9], [10], raises the possibility of pharmacologically delineating the type of signal elicited by the activation of any G protein coupled receptor (GPCR) by inducing/stabilizing a conformation that produces the desired set of responses.

Our conception of how heptahelical receptors signal to their effectors has also changed over the years. Until recently, the prevailing model has been one in which G proteins were considered obligatory signal transducers that conveyed information from activated receptors to effectors by freely shuttling within the plasma membrane [11], [12]. Although this model has the advantage of successfully explaining response amplification via catalytic activation of the G protein, it fails to account for the high level of specificity in receptor–effector coupling. Indeed, given the potential of most G proteins to promiscuously interact with different types of receptors and effectors, shuttling does neither account for coupling selectivity nor spatial and temporal acuity with which GPCRs regulate their effectors [13], [14]. An alternative that obviates this problem is a paradigm which allows for a stable interaction of the G protein both with receptors and effectors. Substantial evidence indicates that this is indeed the case for G protein-mediated signalling in yeast [15] and drosophila [16], and a similar type of organization is also starting to be unveiled for mammalian receptors, Gαβγ subunits and G protein effectors [17], [18], [19]. Since the association of these diverse interacting partners usually takes place before membrane targeting [18], [20], the species reaching the cell surface does so as a constitutive signalling unit. In the following paragraphs we will analyze the possibility that these signalling units may constitute viable targets for development of functionally selective ligands.

Section snippets

Constitutive signalling complexes in mammalian cells

Identification of multimeric protein complexes and characterization of their interaction networks is a vast area of research that is being increasingly applied in modern drug design [21], [22]. The brief synopsis presented herein is by no means comprehensive and its main purpose is to provide evidence that heptahelical receptors, their transducers and effectors form constitutive, membrane-bound signalling units that may be targeted for development of functionally selective therapeutic agents.

Functional selectivity and multiple active receptor states

“Functional selectivity”, “trafficking of stimulus” or “biased agonism”, are terms that were coined in order to describe an increasing number of functional observations in which efficacy is determined by the assay in which ligand responses are tested [2], [3], [4], [5], [6], [93]. They make reference to ligand ability to “select” a subset of outputs among all possible responses associated with receptor stimulation and imply the existence of ligand-specific receptor states, each with its

Conclusion

It is only recently that the existence of multiple active conformations for heptahelical receptors has become widely accepted and that receptor inclusion into constitutive signalling complexes is starting to be considered. Consequently, these properties have not yet been fully explored in the context of drug development. Herein we have provided evidence that a stable, constitutive association of receptors, G proteins and effectors does indeed take place, and have assessed the possibility that

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