G-protein coupled receptor oligomerization in neuroendocrine pathways

doi:10.1016/j.yfrne.2003.10.002

Frontiers in Neuroendocrinology

Volume 24, Issue 4, December 2003, Pages 254-278

https://doi.org/10.1016/j.yfrne.2003.10.002 Get rights and content

Abstract

Protein–protein interactions are fundamental processes for many biological systems including those involving the superfamily of G-protein coupled receptors (GPCRs). A growing body of biochemical and functional evidence supports the existence of GPCR–GPCR homo- and hetero-oligomers. In particular, hetero-oligomers can display pharmacological and functional properties distinct from those of the homodimer or oligomer thus adding another level of complexity to how GPCRs are activated, signal and traffick in the cell. Dimerization may also play a role in influencing the activity of agonists and antagonists. We are only beginning to unravel how and why such complexes are formed, the functional implications of which will have an enormous impact on GPCR biology. Future research that studies GPCRs as dimeric or oligomeric complexes will enhance not only our understanding of GPCRs in cellular function but will also be critical for novel drug design and improved treatment of the vast array of GPCR-related conditions.

Introduction

The realization in the early 1980s that a complex interplay of neurotransmitters is responsible for modulating hypophysiotropic hormone function has greatly contributed towards the expansion of the field of neuroendocrinology. The neurotransmitters, norepinephrine, dopamine, acetylcholine, serotonin, excitatory amino acids (EAAs), and γ-aminobutyric acid (GABA) have all been shown to modulate pituitary hormone secretion, either at the hypothalamic level or by direct action on the pituitary [131]. A fundamental challenge was to understand how these classical neurotransmitters in the brain could integrate their signals with those of the neuropeptides and it was postulated that intramembrane receptor/receptor interactions could occur [6]. The discovery that G-protein coupled receptors (GPCRs) could directly interact to form dimers and higher-order complexes (oligomers) has been a major development in the last decade and their ability to link together to form these complexes has shed some light on how different receptor pathways intersect and cross-react.

Whilst GPCR oligomerization is a not a new concept [61], [101], [136], it is only recently that this has begun to remodel the thinking of researchers in the GPCR field. The currently held view is that oligomerization is a fundamental component of GPCR regulation and function, providing a mechanism by which distinct signalling pathways can be directly linked and receptor functions integrated, which obviously has vast therapeutic implications in human disease. This review will summarize the progress that has been made in our understanding of GPCR oligomerization, the mechanisms involved and the role it plays in receptor function. The contribution to the neuroendocrine system and its regulation through direct linkage of different receptors will be discussed, including how this information may then be translated into novel treatment strategies.

Section snippets

GPCR homo- and hetero-dimerization

Evidence for the existence of GPCR homodimers or oligomers is now substantial, with a large number of reports suggesting that this is a general phenomenon for this receptor superfamily (recently reviewed in [8], [16], [50], [109] and summarized in Table 1). Soon after the first reports describing homo-dimerization emerged, it became apparent that GPCRs could also interact with other members of the receptor superfamily (Table 1). Interactions have been reported between different receptor

Mechanism of oligomerization

Unravelling the structural mechanisms for GPCR dimerization will involve the identification of the dimer interface, which is largely unknown at present. Several models have been proposed with respect to how dimer or oligomer formation occurs. These are (i) covalent bonds (i.e., disulfide bonds) formed between extracellular domains, (ii) interaction of intracellular domains particularly the C-terminal tail (C-tail), and (iii) interactions between transmembrane domains. However, as more data

Regulation of GPCR dimerization

In a single cell several GPCRs could be co-expressed, potentially leading to a complex combination of homo- and heterodimers being formed. However, little is known about how dimerization is regulated. It is possible that homo- or heterodimer formation is influenced by receptor expression levels and/or relative affinities of particular receptor combinations [105], [164]. Alternatively, GPCR dimerization may require and/or be modulated by additional proteins. These two mechanisms may be

Functional significance of GPCR homo-dimerization

It is often difficult to ascertain the functional relevance of GPCR homodimerization, as there are many conflicting reports regarding whether dimers are pre-formed or regulated by ligand binding. In those receptors that display constitutive oligomerization, oligomer formation may occur in the ER and be a requirement for trafficking to the cell surface (possibly by chaperone proteins) [73], [80], [173]. It is also possible that oligomerization may be required for receptor activation and

Functional significance of splice variants

Dimerization of receptors may provide a mechanism by which splice variants and mutant receptors could modulate wild-type receptor function and have physiological effects. Alternatively, it may provide a means to rescue the function of mutant receptors in heterozygous individuals, through dominant-positive receptor interactions.

Functional significance of hetero-dimerization

The observation that hetero-dimerization can result in the formation of receptor units with altered pharmacological and functional properties compared to the individual receptor monomers or homodimers has enormous consequences for patient therapy and the understanding of biological systems as a whole. For certain receptors, hetero-dimerization is essential for receptor function. In the case of the GABA_B receptor, hetero-dimerization between the GABA_BR1 and GABA_BR2 receptors is required for

A role for heterodimerization in vivo?

Despite previous reports providing evidence for GPCR oligomerization and the notion that cross-talk at the level of receptors may explain some of the known physiological interactions occurring within the neuroendocrine system, it has been suggested that this phenomenon is an artefactual observation of protein overexpression in cell culture systems and is of little relevance in vivo [137], [148]. The majority of studies on GPCR dimerization have been performed in recombinant systems, with

Pharmaceutical and clinical implications of dimerization

GPCR hetero-dimerization may represent a way of diversifying the response from GPCRs expressed in a particular cell type, thereby having important implications for drug design and administration of pharmaceuticals used to treat a wide range of GPCR-associated diseases. The formation of heterodimers represents a potential set of novel drug targets that is yet to be exploited, with the link between drug discovery and oligomerization yet to be made. The challenge for the pharmaceutical industry

Conclusions

Even though oligomerization of GPCRs is not considered to be a biological myth, researchers in molecular biology, physiology, or even the pharmaceutical industry have not completely shifted their view in how these receptors are studied and depicted in models. Cross-talk at the level of receptors may explain some of the known physiological interactions occurring within the neuroendocrine system. With regard to GPCR dimerization it is important to understand not only the effect of these

Acknowledgements

This work has been supported by the following grants from the National Health and Medical Research Council (Project Grant 212065). K.E. and K.K. are supported by NHMRC Principle Research Fellow and Peter Doherty Post-doctoral Fellowships, respectively. K.P. is supported by a WAIMR Post-doctoral Fellowship. We also thank Ms. Lisa Beavis, Ms. Ruth Seeber, and Dr. Uli Schmidt for help with the preparation of the manuscript.

References (189)

S AbdAlla et al.
Involvement of the amino terminus of the B (2) receptor in agonist-induced receptor dimerization
J. Biol. Chem.
(1999)
S AbdAlla et al.
The angiotensin II AT2 receptor is an AT1 receptor antagonist
J. Biol. Chem.
(2001)
M.A Ayoub et al.
Monitoring of ligand-independent dimerization and ligand-induced conformational changes of melatonin receptors in living cells by bioluminescence resonance energy transfer
J. Biol. Chem.
(2002)
G.J Babcock et al.
Ligand-independent dimerization of CXCR4, a principal HIV-1 coreceptor
J. Biol. Chem.
(2003)
M Bai et al.
Dimerization of the extracellular calcium-sensing receptor (CaR) on the cell surface of CaR-transfected HEK293 cells
J. Biol. Chem.
(1998)
M Benkirane et al.
Mechanism of transdominant inhibition of CCR5-mediated HIV-1 infection by ccr5delta32
J. Biol. Chem.
(1997)
J Cao et al.
Cloning and characterization of a cDNA encoding a novel subtype of rat thyrotropin-releasing hormone receptor
J. Biol. Chem.
(1998)
Z.J Cheng et al.
Agonist-dependent dissociation of oligomeric complexes of G protein-coupled cholecystokinin receptors demonstrated in living cells using bioluminescence resonance energy transfer
J. Biol. Chem.
(2001)
F Ciruela et al.
Metabotropic glutamate 1alpha and adenosine A1 receptors assemble into functionally interacting complexes
J. Biol. Chem.
(2001)
A Cornea et al.
Gonadotropin-releasing hormone receptor microaggregration: rate monitored by fluorescence resonance energy transfer
J. Biol. Chem.
(2001)

S Cvejic et al.

Dimerization of the delta opioid receptor: implication for a role in receptor internalization

J. Biol. Chem.

(1997)

M.C Dinger et al.

Homodimerization of neuropeptide y receptors investigated by fluorescence resonance energy transfer in living cells

J. Biol. Chem.

(2003)

B Duthey et al.

A single subunit (GB2) is required for G-protein activation by the heterodimeric GABA(B) receptor

J. Biol. Chem.

(2002)

S.W Edwards et al.

Localization of G-protein-coupled receptors in health and disease

Trends Pharmacol. Sci.

(2000)

K.A Eidne et al.

Applications of novel resonance energy transfer techniques to study dynamic hormone receptor interactions in living cells

Trends Endocrinol. Metab.

(2002)

J.L Elmhurst et al.

The splice variant D3nf reduces ligand binding to the D3 dopamine receptor: evidence for heterooligomerization

Brain Res. Mol. Brain Res.

(2000)

S Ferre et al.

Adenosine as a volume transmission signal. A feedback detector of neuronal activation

Prog. Brain Res.

(2000)

T Galvez et al.

Mapping the agonist-binding site of GABAB type 1 subunit sheds light on the activation process of GABAB receptors

J. Biol. Chem.

(2000)

L Gama et al.

Heterodimerization of calcium sensing receptors with metabotropic glutamate receptors in neurons

J. Biol. Chem.

(2001)

A.R Genazzani et al.

Opioid control of luteinizing hormone secretion in humans

J. Steroid Biochem.

(1989)

S.R George et al.

A transmembrane domain-derived peptide inhibits D1 dopamine receptor function without affecting receptor oligomerization

J. Biol. Chem.

(1998)

S.R George et al.

Oligomerization of mu- and delta-opioid receptors. Generation of novel functional properties

J. Biol. Chem.

(2000)

I Gomes et al.

Oligomerization of opioid receptors

Methods

(2002)

W Guo et al.

The fourth transmembrane segment forms the interface of the dopamine D2 receptor homodimer

J. Biol. Chem.

(2003)

M Handel et al.

Selective targeting of somatostatin receptor 3 to neuronal cilia

Neuroscience

(1999)

A.C Hanyaloglu et al.

Homo- and hetero-oligomerization of thyrotropin-releasing hormone (TRH) receptor subtypes. Differential regulation of beta-arrestins 1 and 2

J. Biol. Chem.

(2002)

E Hazum et al.

Increased biological activity of dimers of oxymorphone and enkephalin: possible role of receptor crosslinking

Biochem. Biophys. Res. Commun.

(1982)

E Hazum et al.

Gonadotropin releasing hormone activation is mediated by dimerization of occupied receptors

Biochem. Biophys. Res. Commun.

(1985)

L He et al.

Regulation of opioid receptor trafficking and morphine tolerance by receptor oligomerization

Cell

(2002)

T.E Hebert et al.

A peptide derived from a beta2-adrenergic receptor transmembrane domain inhibits both receptor dimerization and activation

J. Biol. Chem.

(1996)

J Hillion et al.

Coaggregation, cointernalization, and codesensitization of adenosine A2A receptors and dopamine D2 receptors

J. Biol. Chem.

(2002)

A Horita

An update on the CNS actions of TRH and its analogs

Life Sci.

(1998)

H Issafras et al.

Constitutive agonist-independent CCR5 oligomerization and antibody-mediated clustering occurring at physiological levels of receptors

J. Biol. Chem.

(2002)

H Itadani et al.

Cloning and characterization of a new subtype of thyrotropin-releasing hormone receptors

Biochem. Biophys. Res. Commun.

(1998)

B.A Jordan et al.

Opioids and their complicated receptor complexes

Neuropsychopharmacology

(2000)

T Kamiya et al.

Oligomerization of adenosine A2A and dopamine D2 receptors in living cells

Biochem. Biophys. Res. Commun.

(2003)

B.L Kieffer

Opioids: first lessons from knockout mice

Trends Pharmacol. Sci.

(1999)

K.M Kroeger et al.

Constitutive and agonist-dependent homo-oligomerization of the thyrotropin-releasing hormone receptor. Detection in living cells using bioluminescence resonance energy transfer

J. Biol. Chem.

(2001)

R Latif et al.

Ligand-dependent inhibition of oligomerization at the human thyrotropin receptor

J. Biol. Chem.

(2002)

C Lavoie et al.

Beta 1/beta 2-adrenergic receptor heterodimerization regulates beta 2-adrenergic receptor internalization and ERK signaling efficacy

J. Biol. Chem.

(2002)

Y Liang et al.

Organization of the G protein-coupled receptors rhodopsin and opsin in native membranes

J. Biol. Chem.

(2003)

L.E Limbird et al.

Negative cooperativity among beta-adrenergic receptors in frog erythrocyte membranes

J. Biol. Chem.

(1976)

K Liu et al.

On the origin of mRNA encoding the truncated dopamine D3-type receptor D3nf and detection of D3nf-like immunoreactivity in human brain

J. Biol. Chem.

(1994)

R Maggio et al.

Reconstitution of functional muscarinic receptors by co-expression of amino- and carboxyl-terminal receptor fragments

FEBS Lett.

(1993)

R Maggio et al.

Functional role of the third cytoplasmic loop in muscarinic receptor dimerization

J. Biol. Chem.

(1996)

M Margeta-Mitrovic et al.

A trafficking checkpoint controls GABA(B) receptor heterodimerization

Neuron

(2000)

S AbdAlla et al.

AT1-receptor heterodimers show enhanced G-protein activation and altered receptor sequestration

Nature

(2000)

S AbdAlla et al.

Increased AT (1) receptor heterodimers in preeclampsia mediate enhanced angiotensin II responsiveness

Nat. Med.

(2001)

D Accili et al.

A targeted mutation of the D3 dopamine receptor gene is associated with hyperactivity in mice

Proc. Natl. Acad. Sci. USA

(1996)

L.F Agnati et al.

Molecular mechanisms and therapeutical implications of intramembrane receptor/receptor interactions among heptahelical receptors with examples from the striatopallidal GABA neurons

Pharmacol. Rev.

(2003)

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^☆: Abbreviations used: ATII, angiotensin II; AT1R, type 1 angiotensin receptor; BRET, bioluminescence resonance energy transfer; CCR5, chemokine receptor 5; CFP, cyan fluorescent protein; ECL, extracellular loop; ER, endoplasmic reticulum; EYFP, enhanced yellow fluorescent protein; FITC, fluorescein isothiocyanate; FRET, fluorescence resonance energy transfer; FSH, follicle stimulating hormone; GFP, green fluorescent protein; GH, growth hormone; GnRH, gonadotropin releasing hormone; GPCR, G-protein coupled receptor; GRK, G-protein coupled receptor kinase; ICL, intracellular loop; LH, luteinizing hormone; α-MSH, α-melanocyte stimulating hormone; MT1R, melatonin receptor 1; MT2R, melatonin receptor 2; mGluR1, metabotropic glutamate receptor 1; PKC, protein kinase C; PRL, prolactin; RAMP, receptor activity modifying protein; RFP, red fluorescent protein; Rluc, Renilla luciferase; SST, somatostatin; SSTR, somatostatin receptor; TM, transmembrane; TR-FRET, time-resolved FRET; TRH, thyrotropin releasing hormone; TSH, thyroid stimulating hormone; trunc, truncated; P₂Y₁ receptor, P₂ ATP purinoceptor; VFTM, venus fly-trap motif; VIP, vasoactive intestinal polypeptide; YFP, yellow fluorescent protein.

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G-protein coupled receptor oligomerization in neuroendocrine pathways☆

Abstract

Introduction

Section snippets

GPCR homo- and hetero-dimerization

Mechanism of oligomerization

Regulation of GPCR dimerization

Functional significance of GPCR homo-dimerization

Functional significance of splice variants

Functional significance of hetero-dimerization

A role for heterodimerization in vivo?

Pharmaceutical and clinical implications of dimerization

Conclusions

Acknowledgements

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

Trends Pharmacol. Sci.

Trends Endocrinol. Metab.

Brain Res. Mol. Brain Res.

Prog. Brain Res.

J. Biol. Chem.

J. Biol. Chem.

J. Steroid Biochem.

J. Biol. Chem.

J. Biol. Chem.

Methods

J. Biol. Chem.

Neuroscience

J. Biol. Chem.

Biochem. Biophys. Res. Commun.

Biochem. Biophys. Res. Commun.

Cell

J. Biol. Chem.

J. Biol. Chem.

Life Sci.

J. Biol. Chem.

Biochem. Biophys. Res. Commun.

Neuropsychopharmacology

Biochem. Biophys. Res. Commun.

Trends Pharmacol. Sci.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

FEBS Lett.

J. Biol. Chem.

Neuron

AT1-receptor heterodimers show enhanced G-protein activation and altered receptor sequestration

Nature

Increased AT (1) receptor heterodimers in preeclampsia mediate enhanced angiotensin II responsiveness

Nat. Med.

A targeted mutation of the D3 dopamine receptor gene is associated with hyperactivity in mice

Proc. Natl. Acad. Sci. USA

Molecular mechanisms and therapeutical implications of intramembrane receptor/receptor interactions among heptahelical receptors with examples from the striatopallidal GABA neurons

Pharmacol. Rev.