Trends in Neurosciences
ReviewFunctional relevance of neurotransmitter receptor heteromers in the central nervous system
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.).
References (54)
Regulation of heptaspanning-membrane-receptor function by dimerization and clustering
Trends Biochem. Sci.
(2003)GPCR interacting proteins
Pharmacol. Ther.
(2004)How receptor mosaics decode transmitter signals. Possible relevance of cooperativity
Trends Biochem. Sci.
(2005)Neurotransmitters
Curr. Biol.
(2005)Glutamate receptors: brain function and signal transduction
Brain Res. Rev.
(1998)Heterodimerization of G-protein-coupled receptors in the CNS
Curr. Opin. Pharmacol.
(2001)GABAB receptors – the first 7TM heterodimers
Trends Pharmacol. Sci.
(1999)Oligomerization of mu- and delta-opioid receptors. Generation of novel functional properties
J. Biol. Chem.
(2000)Coaggregation, cointernalization, and codesensitization of adenosine A2A receptors and dopamine D2 receptors
J. Biol. Chem.
(2002)Adenosine A2A-dopamine D2 receptor-receptor heteromerization: qualitative and quantitative assessment by fluorescence and bioluminescence energy transfer
J. Biol. Chem.
(2003)
Oligomerization of opioid receptors: generation of novel signaling units
Curr. Opin. Pharmacol.
Dual regulation of NMDA receptor functions by direct protein-protein interactions with the dopamine D1 receptor
Cell
Effect of N-methyl-D-aspartate on motor activity and in vivo adenosine striatal outflow in the rat
Eur. J. Pharmacol.
Adenosine as a neuromodulator and as a homeostatic regulator in the nervous system: different roles, different sources and different receptors
Neurochem. Int.
Astrocytic control of glutamatergic activity: astrocytes as stars of the show
Trends Neurosci.
The selective mGlu(5) receptor agonist CHPG inhibits quinpirole-induced turning in 6-hydroxydopamine-lesioned rats and modulates the binding characteristics of dopamine D(2) receptors in the rat striatum: interactions with adenosine A(2a) receptors
Neuropsychopharmacology
Regulation of AMPA receptors during synaptic plasticity
Trends Neurosci.
Molecular mechanisms and therapeutical implications of intramembrane receptor/receptor interactions among heptahelical receptors with examples from the striatopallidal GABA neurons
Pharmacol. Rev.
Novel neurotransmitters and their neuropsychiatric relevance
Am. J. Psychiatry
Guide to receptors and channels (GRAC)
Br. J. Pharmacol.
Subtypes of gamma-aminobutyric acid A receptors: classification on the basis of subunit structure and receptor function
Pharmacol. Rev.
Brain nicotinic acetylcholine receptors: native subtypes and their relevance
Trends Pharmacol. Sci.
The GDNF family: signalling, biological functions and therapeutic value
Nat. Rev. Neurosci.
Neurotrophins and their receptors: a convergence point for many signalling pathways
Nat. Rev. Neurosci.
G-protein-coupled receptor oligomerization and its potential for drug discovery
Nat. Rev. Drug Discov.
Heterodimerization of G protein-coupled receptors: specificity and functional significance
Pharmacol. Rev.
Oligomerization of G-protein-coupled transmitter receptors
Nat. Rev. Neurosci.
Cited by (131)
Post-learning caffeine administration improves ‘what-when’ and ‘what-where’ components of episodic-like memory in rats
2022, Behavioural Brain ResearchOf adenosine and the blues: The adenosinergic system in the pathophysiology and treatment of major depressive disorder
2021, Pharmacological ResearchCitation Excerpt :While this is not entirely surprising, considering how relatively recent the evidence of functional heteromers is, it is the most significant gap in the literature and one that might hold considerable interest. This is all the more surprising when considering that adenosine receptors are known to form functional heteromers not just with one another (e.g., A1R-A2AR [329]), but also with receptors from other systems deeply impacted by MDD [49,330–333]. Moreover, these heteromers have been shown to be involved in the regulation of important processes, whose dysfunction may be key in the development and/or treatment of this disorder [334].
Pharmacological interactions between adenosine A<inf>2A</inf> receptor antagonists and different neurotransmitter systems
2020, Parkinsonism and Related DisordersDynamic roles for the N-terminus of the yeast G protein-coupled receptor Ste2p
2017, Biochimica et Biophysica Acta - Biomembranes