Trends in Neurosciences
Volume 30, Issue 9, September 2007, Pages 440-446
Journal home page for Trends in Neurosciences

Review
Functional relevance of neurotransmitter receptor heteromers in the central nervous system

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The existence of neurotransmitter receptor heteromers is becoming broadly accepted and their functional significance is being revealed. Heteromerization of neurotransmitter receptors produces functional entities that possess different biochemical characteristics with respect to the individual components of the heteromer. Neurotransmitter receptor heteromers can function as processors of computations that modulate cell signaling. Thus, the quantitative or qualitative aspects of the signaling generated by stimulation of any of the individual receptor units in the heteromer are different from those obtained during coactivation. Furthermore, recent studies demonstrate that some neurotransmitter receptor heteromers can exert an effect as processors of computations that directly modulate both pre- and postsynaptic neurotransmission. This is illustrated by the analysis of striatal receptor heteromers that control striatal glutamatergic neurotransmission.

Introduction

Although it has had some initial resistance from the scientific community, the existence of neurotransmitter receptor heteromers is now becoming accepted. This acceptance implies changing and broadening of classical notions about neurotransmission. Thus, neurotransmitter receptors cannot only be considered as single functional units, but as forming part of multimolecular aggregates localized in the plane of the plasma membrane (also called ‘horizontal molecular networks’), which can contain other interacting proteins, including receptors for the same or other neurotransmitters 1, 2, 3, 4. At the outset, we should define the term ‘neurotransmitter receptor heteromer’. The term ‘neurotransmitter’ is continuously evolving, and the initial restrictive criteria that enabled the inclusion of acetylcholine and monoamines have been substituted by more general definitions. Here, we adopt the broad definition of neurotransmitter, coined by Snyder and Ferris [5] – that is, ‘a molecule, released by neurons or glia, which physiologically influences the electrochemical state of adjacent cells’. This definition enables the inclusion of previously ill-defined terms, such as ‘neuromodulator’ and ‘neuropeptide’. It also enables the inclusion of lipids, such as endocannabinoids; proteins, such as neurotrophic factors; and gaseous messengers, such as nitric oxide 5, 6. Here, the term ‘neurotransmitter receptor’ refers to the minimal functional unit activated by a neurotransmitter and localized in the plasma membrane (i.e. a transmembrane neurotransmitter receptor). This definition includes G-protein-coupled receptors (GPCRs; heptahelical or metabotropic receptors), ligand-gated ion channels (ionotropic receptors) and catalytic receptors, such as receptors for neurotrophins and glial cell line-derived neurotrophic factor (GDNF) family ligands [7].

A receptor heteromer can be defined as a complex molecule made up of different receptor molecules for the same or different neurotransmitters. This definition includes the possibility of receptor heterodimers and receptor multimers (i.e. heteromers of two or more molecules of different receptors). A receptor homomer, by contrast, is a complex molecule composed of two or more identical receptor molecules. The terms ‘receptor heteromer’ and ‘receptor homomer’ imply a direct physical interaction between the receptor molecules and does not include receptors indirectly linked by intermediate proteins, such as the N-methyl-d-aspartate glutamate receptor (NMDAR) and group I metabotropic glutamate receptors, which are linked by four serially connected scaffold proteins [postsynaptic density (PSD) 95 protein, guanylate kinase-associated protein, and the proteins Shank and Homer] [3].

It is important to make a distinction between receptor heteromer and ‘heteromeric receptor’, the latter being an oligomeric receptor for which the minimal functional unit is composed of different protein subunits, such as most ligand-gated ion channels [e.g. γ-aminobutyric-acid A receptor (GABAAR), NMDAR and the non-α7 nicotinic acetylcholine receptor (non-α7 nAChR)] 8, 9, 10. In addition, some catalytic receptors for neurotrophic factors, such as receptors for GDNF-family ligands, are composed of different subunits, which are either responsible for the association with the ligand or for the catalytic response [11]. As discussed later, there are examples of receptor heteromers containing a GPCR and a heteromeric ligand-gated ion channel (i.e. receptor heteromers with heteromeric receptors). A homomeric receptor, by contrast, is an oligomeric receptor for which the minimal functional unit is composed of the same subunit (e.g. the α7 nAChR) [10] or a neurotrophin receptor, which requires ligand-induced dimerization to become functional [12].

Here, we review the evidence for the existence and functional relevance of neurotransmitter receptor heteromers in the central nervous system (CNS). We do not include an extensive analysis of all neurotransmitter receptor heteromers so far discovered, nor their potential for drug discovery, because this has been covered previously by other reviews 2, 13, 14. The examples presented here emphasize in particular the role of neurotransmitter receptor heteromers as processors of computations that mediate cell signaling and pre- and postsynaptic neurotransmission.

Section snippets

Neurotransmitter receptors do heteromerize

Early evidence showed that GPCRs are able to form receptor homodimers and also higher-order homomultimers. It has subsequently been shown that most, if not all, members of this neurotransmitter receptor superfamily can exist as homodimers 13, 15, 16. The first indication of the existence of neurotransmitter receptor heteromers was obtained with radioligand binding experiments, which demonstrated biochemical interactions between different GPCRs in brain membrane preparations [2]. In interactions

Neurotransmitter receptor heteromers as processors of computations that modulate cell signaling

Receptor heteromerization provides functional entities which possess different biochemical properties with respect to the individual components of the heteromer. A receptor unit in the heteromer can display several biochemical properties (see later), which can be simply dependent on the presence of the other unit or on co-stimulation of the two (or more) receptor units in the heteromer. Changes in ligand binding characteristics are a common property of neurotransmitter receptor heteromers, thus

Neurotransmitter receptor heteromers as processors of computations that modulate pre- and postsynaptic neurotransmission

Some neurotransmitter receptor heteromers function as processors of computations that modulate signaling that is crucially involved in the modulation of pre- and postsynaptic neurotransmission. Therefore, these receptor heteromers are in a position to control neurotransmission directly. The role of heteromers as processors of computations governing neurotransmission is illustrated here by analyzing the role of different A2AR heteromers in the modulation of striatal glutamatergic

Conclusions and future perspectives

Recent and compelling experimental data have demonstrated the existence and functional significance of neurotransmitter receptor heteromers. Although FRET, BRET and other techniques clearly demonstrate protein–protein interactions in artificial cell systems, one concern has been that neurotransmitter receptor heteromers might be an artifact of these experimental settings. Nevertheless, finding a ‘biochemical fingerprint’ of a neurotransmitter receptor heteromer previously found in an artificial

Acknowledgements

Supported by the Intramural Research funds of the National Institute on Drug Abuse, NIH and grants from the Spanish Ministerio de Ciencia y Tecnología (SAF2005-00903 to F.C. and SAF2006-05481 to R.F.).

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