Constitutive activity of G protein coupled receptors and drug action

https://doi.org/10.1016/S0031-6865(99)00042-4Get rights and content

Introduction

An interesting and new concept in G protein coupled receptor (GPCR)-mediated drug action is the occurrence of constitutive activity of GPCRs in the absence of agonist stimulation. Originally reported for the δ-opioid receptor in NG108-15 cells (Costa and Herz, 1989), this GPCR activity has now been described for a variety of GPCRs (Milligan et al., 1995). Concomitant with the notion of agonist-independent signalling it has been realised that the constitutive GPCR activity can be inhibited by some antagonists (inverse agonists), but not by all antagonists (neutral antagonists) introducing the need for a pharmacological reclassification of GPCR antagonists (Milligan et al., 1995). Moreover, as previously described for agonists also for inverse agonist a full spectrum of (negative) intrinsic activity from −1 to 0 can be observed (Milligan et al., 1995; Leurs et al., 1998). Neutral antagonists, i.e., compounds with actually no intrinsic activity, are quite rare. Nevertheless, for some GPCRs, ligands with virtually no (negative) intrinsic activity are found. For example, the H2 receptor (the first described H2 antagonists burimamide) has been identified as a ligand with very low (Alewijnse et al., 1998) or no intrinsic activity (Smit et al., 1996). Burimamide is able to block the effects of both an agonist (histamine) and an inverse agonist (cimetidine) on the cAMP levels in CHO cells expressing the H2 receptor (Fig. 1), with apparent pKB values that match its pKi value (Alewijnse et al., 1998).

Section snippets

Constitutive activity and the two-state model

To explain the above described findings the GPCR protein is thought to isomerise between (at least) two different states, an inactive (R) and active (R*) conformation. In this oversimplified scheme the R* state is considered to be responsible for effective G protein activation and the equilibrium between R and R* determines the level of basal, constitutive GPCR signalling (Milligan et al., 1995; Kenakin, 1996; Leurs et al., 1998). Agonist binding is thought to shift the equilibrium towards R*,

Constitutive activity in a cellular context

It is accepted for some time that agonists can have different intrinsic activities in different cell systems. Similarly, the degree of constitutive GPCR activity and the concomitant inverse agonistic behaviour of GPCR ligands are also highly dependent upon the cellular context. As for GPCR agonism, one of the main determinants for constitutive GPCR signalling is the expression level of the respective GPCR. As can be seen in Fig. 2A, the transient expression of the histamine H1 receptor in COS-7

CAM GPCRs and human disease

The structural features of the GPCR that determine the level of constitutive activity are poorly understood. Important information has been obtained from studies, with so-called constitutively active mutant (CAM) receptors. Studies with adrenergic CAM receptors have indicated that the intracellular loop close to TM6 is of main importance (Samama et al., 1993). However, recent data suggest that mutations throughout the GPCR protein can result in constitutive activation (Pauwels and Wurch, 1998).

Agonist-like auto-antibodies and inverse agonists

Agonist-independent GPCR activation can in vivo also occur by other means. The presence of auto-antibodies against GPCRs with agonist-like properties has been associated with human disorders (Borda and Sterinborda, 1996; Hoebeke, 1996), such as Graves' disease (antibodies with TSH-like activity), Chagas disease (antibodies against β1-, β2 adrenergic and muscarinic m2 receptors), idiopathic dilated cardiomyopathy (anti-muscarinic m2 and anti-β1 receptor) and forms of malignant hypertension

Long-term exposure to inverse agonists

Long-term agonist exposure is known to result in the downregulation of GPCRs. Extending the concept of inverse agonism to GPCR regulation, long-term exposure of cells expressing constitutively active GPCRs to inverse agonists should result in an upregulation of GPCRs. Inverse agonist treatment of cells expressing β2-CAM receptors indeed results in sensitisation of adenylyl cyclase and is accompanied by an increase in binding sites (Pei et al., 1994). Also constitutively active wild-type

Conclusions

The new concept of constitutive GPCR activity has received considerable attention in recent years. For a proper understanding of drug action the molecular aspects underlying the negative intrinsic activity of inverse agonists should be understood. It is clear that constitutive activity of GPCRs highly depends on the `cellular context' and, thus, will be tissue specific and differ among species and individuals. Disorders, originating from constitutively signalling of GPCRs (e.g., due to

Acknowledgements

The research of the authors is supported by the EU BIOMED 2 programme `Inverse Agonism. Implications for drug research'.

First page preview

First page preview
Click to open first page preview

References (37)

  • G Milligan et al.

    Inverse agonism: pharmacological curiosity or potential therapeutic strategy

    Trends Pharmacol. Sci.

    (1995)
  • L.S Robbins et al.

    Pigmentation phenotypes of variant extension locus alleles result from point mutations that alter MSH receptor function

    Cell

    (1993)
  • P.R Robinson et al.

    Constitutively active mutants of rhodopsin

    Neuron

    (1992)
  • P Samama et al.

    A mutation-induced activated state of the β2-adrenergic receptor

    J. Biol. Chem.

    (1993)
  • M Tiberi et al.

    High agonist-independent activity is a distinguishing feature of the dopamine D1B receptor subtype

    J. Biol. Chem.

    (1994)
  • F Waagstein et al.

    Beneficial effects of metoprolol in idiopathic dilated cardiomyopathy

    Lancet

    (1993)
  • B.C Yoburn et al.

    Opioid antagonist-induced receptor upregulation: effects of concurrent agonist administration

    Brain Res.

    (1994)
  • E.J Adie et al.

    Regulation of basal adenylate cyclase activity in neuroblastoma×glioma hybrid, NG108-15, cells transfected to express the human beta 2 adrenoceptor: evidence for empty receptor stimulation of the adenylate cyclase cascade

    Biochem. J.

    (1994)
  • Cited by (19)

    • Aβ peptides stabilize GPCRs in inactive form and trigger inverse agonism in Alzheimer's disease

      2022, Biochimie
      Citation Excerpt :

      This process is explained in Fig. 1. There is sufficient evidence that GPCRs undergo inverse agonism due to non-specific binding [32–36]. Furthermore, Aβ is known to bind GPCRs, like amylin [37] and formyl receptors [38].

    • Modeling and simulation of inverse agonism dynamics

      2010, Methods in Enzymology
      Citation Excerpt :

      In Chidiac (2002), a two-state receptor model is described, including receptor desensitization. As is common in cell signaling and pharmacological modeling studies, the analysis is at equilibrium; this is also true of the extended cubic ternary complex model analysis in Negus (2006), the simplified model in Leurs et al. (2000), and the inverse agonism mechanism and consitutively active mutant models in Strange (2002). Steady-state results of course provide only a subset of the information which one can gain from a dynamic model.

    • Constitutive activity of the histamine H <inf>1</inf> receptor

      2010, Methods in Enzymology
      Citation Excerpt :

      G proteins preferentially bind active (R*) receptor states, thereby shifting the equilibrium between R and R* conformations toward the latter (Burstein et al., 1995a, 1997). Indeed, coexpressing extra Gα11, Gαq, or Gβγ proteins increased constitutive H1R signaling, which could be repressed by the full inverse agonist mepyramine (Fig. 7.3B; Bakker et al., 2007; Fitzsimons et al., 2004; Leurs et al., 2000). Importantly, Gαq protein levels are upregulated in the nasal mucosa of a guinea pig model of nasal hyper-responsiveness (Chiba et al., 2002).

    View all citing articles on Scopus
    View full text