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FEBS Letters 589 (2015) 1607–1619

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Review Regulation of neuronal communication by -coupled receptors ⇑ Yunhong Huang, Amantha Thathiah

VIB Center for the Biology of Disease, Leuven, Belgium Center for Human Genetics (CME) and Leuven Institute for Neurodegenerative Diseases (LIND), University of Leuven (KUL), Leuven, Belgium

article info abstract

Article history: Neuronal communication plays an essential role in the propagation of information in the brain and Received 31 March 2015 requires a precisely orchestrated connectivity between . Synaptic transmission is the mech- Revised 5 May 2015 anism through which neurons communicate with each other. It is a strictly regulated process which Accepted 5 May 2015 involves membrane depolarization, the cellular machinery, release Available online 14 May 2015 from synaptic vesicles into the synaptic cleft, and the interaction between ion channels, G Edited by Wilhelm Just protein-coupled receptors (GPCRs), and downstream effector molecules. The focus of this review is to explore the role of GPCRs and G protein-signaling in , to highlight the func- tion of GPCRs, which are localized in both presynaptic and postsynaptic membrane terminals, in reg- Keywords: G protein-coupled receptors ulation of intrasynaptic and intersynaptic communication, and to discuss the involvement of G-proteins astrocytic GPCRs in the regulation of neuronal communication. Neuronal communication Ó 2015 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved. Synaptic transmission Signaling Astrocytes Neurons

1. Introduction serotonin; (3) the ; and (4) the membrane-permeable mediators nitric oxide, endocannabinoids, Efficient neuronal communication is crucial for sensory percep- and other gaseous and lipidic neurotransmitters [2]. The classical tion, stimulus transduction, information processing, and motor neurotransmitters are released by calcium (Ca2+)-triggered exocy- output in every vertebrate animal. This process requires a tosis, allowing rapid neuronal communication. The monoaminergic well-defined connection between neurons to ensure the integra- neurotransmitters are also released by Ca2+-dependent exocytosis tion of both external and internal sensory input and the generation from terminals, but these neurotransmitters can diffuse over of appropriate responses to meet the demands of the individual’s longer distances and have moderate to fast signaling kinetics. The environment [1]. Neurons communicate with each other through neuropeptides undergo Ca2+-dependent exocytosis, are not two principal mechanisms: the of chemical messengers restricted to certain neuronal structures, and can diffuse over very called neurotransmitters at chemical and the direct long distances with long-lasting effects. In contrast, the membrane transfer of intercellular signals via gap junctions at electrical permeable mediators are released immediately after synthesis and synapses [2]. Electrical coupling between neurons is very rare in are not stored in vesicles. The signaling duration and range of dif- the vertebrate central nervous system (CNS). Therefore, most neu- fusion are both short. Collectively, chemical synapses consist of ronal communication in vertebrate systems depends on the release distinct types of vesicles, which differ in their morphology, release of a wide variety of neurotransmitters, which can be divided into kinetics, and distribution; however, the cellular machinery is con- four classes: (1) the classical neurotransmitters glutamate, served for fusion events and requires Ca2+-mediated exocytosis [3]. c-aminobutyric acid (GABA), , , adenosine, The released neurotransmitters bind to and activate receptors and adenosine-triphosphate (ATP); (2) the monoaminergic neuro- on postsynaptic membranes. Neurotransmitter-gated ion channels, transmitters , noradrenaline, adrenaline, , and or ionotropic receptors, are responsible for fast synaptic transmis- sion [4]. These receptors are located close to the neurotransmitter release site and decode chemical signals into electrical responses in ⇑ Corresponding author at: VIB Center for the Biology of Disease, Leuven, postsynaptic neurons. Slow synaptic transmission is mediated by Belgium. E-mail addresses: [email protected] (Y. Huang), amantha. GPCRs [5]. These receptors are indirectly linked to ion channels [email protected] (A. Thathiah). and may also be distally located relative to the neurotransmitter

http://dx.doi.org/10.1016/j.febslet.2015.05.007 0014-5793/Ó 2015 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved. 1608 Y. Huang, A. Thathiah / FEBS Letters 589 (2015) 1607–1619 release site, where they activate biochemical signaling cascades subtypes as well as G protein-independent signaling pathways. with multiple downstream effectors. Many terminals, such Recent breakthrough developments in protein engineering and as sympathetic , auditory giant synapses, and hippocampal crystallography studies have begun to elucidate the structural mossy fibers, are regulated by both GPCRs and ionotropic receptors basis by which this is accomplished and have provided significant [6]. Consequently, the actions of GPCRs and ionotropic receptors insight into how protein structure dictates the unique functional can differ greatly with variations in affinity, activation properties of these complex signaling molecules [14,15]. For most and desensitization properties determining the effect at a given GPCRs, binding of the endogenous or neurotransmitter synaptic terminal (see Fig. 1). promotes a conformational change that results in the activation GPCRs are the largest family of membrane proteins. More than of receptor-associated heterotrimeric G proteins and consequent 800 GPCRs have been identified in the human genome, including downstream signaling [14]. Heterotrimeric G proteins are com- over 370 non-sensory GPCRs. More than 90% of these GPCRs are posed of three subunits, a, b and c. binding catalyzes the expressed in the brain, where they play important roles in cogni- exchange of bound guanosine diphosphate (GDP) on the Ga sub- tion, mood, appetite, pain, and synaptic transmission through unit for guanosine triphosphate (GTP). The exchange in the gua- presynaptic and postsynaptic modulation of neurotransmitter nine nucleotides leads to a reduction in the affinity of the Ga release [7]. GPCR ligands include a wide range of molecules such subunit for the Gbc complex and functional dissociation of the het- as photons, ions, biogenic amines, peptide and non-peptide neuro- erotrimer [16]. The dissociated G protein subunits can then trans- transmitters, , growth factors, and lipids [8]. Accordingly, mit signals to effector proteins, such as enzymes and ion channels, GPCRs are involved in various physiological functions including resulting in rapid changes in the concentration of intracellular sig- vision, taste, olfaction, sympathetic and parasympathetic nervous naling molecules, cyclic adenosine monophosphate (cAMP), cyclic functions, metabolism, and immune regulation and are important guanosine monophosphate (cGMP), inositol phosphates, diacyl- therapeutic targets in many human diseases including diabetes, glycerol, arachidonic acid, and cytosolic ions, which affect a variety neurodegeneration, cardiovascular disease, and psychiatric disor- of cellular functions [17]. The focus of this review is to discuss the ders [9–11]. Based on sequence and structural similarities, GPCRs regulation of neuronal communication at the by GPCR sig- are phylogenetically classified into five main families: Rhodopsin naling pathways. (701 members), Glutamate (15 members), Adhesion (24 members), Frizzled/Taste2 (24 members), and Secretin (15 members), with 2. Neuronal GPCRs each family exhibiting unique ligand binding properties [12,13]. All GPCRs are characterized by the presence of seven 2.1. Metabotropic glutamate receptors (mGluRs) transmembrane-spanning a-helical segments separated by alter- nating intracellular and extracellular loop regions [14]. Despite Glutamate belongs to the first class of classical neurotransmit- these similarities, individual GPCRs display unique combinations ters. It functions as the major excitatory neurotransmitter in the of signal-transduction activities that involve multiple G protein brain. Glutamine, the precursor of glutamate, is generated in

Ca2+ Ca2+ Ca2+ Presynapc Ca2+ Ca2+ terminal

Astrocyte

uptake

Postsynapc terminal release

G protein signaling

Ca2+

EPSCs Downstream signaling Gene transcripon

GPCR NMDAR Voltage-gated calcium channels Glutamate System N transporter Ion channel

GPCR AMPAR Glutamate transporters Glutamine System A transporter

Fig. 1. Neuronal and astrocytic GPCRs modulate glutamatergic neurotransmission. Astrocytes produce glutamine, which can be directly secreted from astrocytes through System N (SN1) transporters. Glutamine is then taken up by neurons at presynaptic membrane terminals by system A transporter (SA1 and SA2) influx for the synthesis of glutamate. Glutamate is then packaged into synaptic vesicles prior to release in the synaptic cleft. Elevation of presynaptic intracellular Ca2+ levels triggers fusion and release. The process is regulated by the GPCR-mediated activation of G protein-signaling cascades which promotes/inhibits Ca2+ influx or the release of intracellular Ca2+ stores. In the synaptic cleft, glutamate binds to activated NMDARs or AMPARs, resulting in a Ca2+ influx and the induction of fast excitatory postsynaptic currents (EPSCs). Certain activated GPCRs mediate the release of Ca2+ from intracellular Ca2+ stores to increase of intracellular Ca2+ levels, which evoke slow EPSCs. Activation of GPCRs may also lead to gene transcription and the modulation of . Astrocytic GPCRs can modulate sodium-dependent glutamate transporters which regulates glutamate uptake by astrocytes. Glutamate can also be released directly from astrocytes via ion channels, such as TREK-1 and Best1, which are involved in the activation of certain GPCRs. Y. Huang, A. Thathiah / FEBS Letters 589 (2015) 1607–1619 1609 astrocytes. It is transferred from astrocytes by system N trans- LY354740, indicating that activation of both receptors contribute porter (SN1) efflux [18] to neurons by system A transporter (SA1 to the anxiolytic-like actions of mGluR2/3 agonists. The elevated and SA2) influx for the synthesis of glutamate. Glutamate released plus maze test is widely used to evaluate anxiety-associated brain from presynaptic terminals, binds to postsynaptic glutamate regions including limbic regions, , amygdala, dorsal receptors, which are involved in the modulation of neuronal exci- raphe nucleus, which could be controlled by various neurotrans- tation. Interestingly, the lipid mediator sphingosine 1-phosphate mitters, such as glutamate and GABA [40]. It has been reported that

(S1P) has been shown to induce and potentiate glutamate release the activation of group II mGluRs-mediated Gai/o signaling, results from presynaptic terminals [19]. Two categories of glutamate in an attenuation of the Ca2+ influx and a reduction in the release of receptors have been indentified: ionotropic glutamate receptors glutamate and GABA [41]. Collectively, the evidence suggests that and metabotropic glutamate receptors. Ionotropic glutamate group II mGluRs-mediated neurotransmission is involved in the receptors include four classes of receptors: the regulation of anxiety.

N-methyl-D-aspartate (NMDA), a-amino-3-hydroxy-5-methyl-4-i Similar to group II mGluRs, group III mGluRs couple to Gi/o pro- soxazolepropionic acid (AMPA), Delta, and kainate receptors, teins. Due to the distribution of these receptors in both presynaptic which function as ion channels and trigger postsynaptic currents terminals of glutamatergic and GABAergic neurons, they modulate upon glutamate-mediated synaptic activation. In contrast, both excitatory and inhibitory neurotransmission; however, the mGluRs are a group of GPCRs which initiate G protein-signaling modulatory activity depends on the brain region and/or cell-type cascades following receptor activation. Eight different types of involved. In the rat subthalamic nucleus, activation of group III mGluRs have been identified in humans. Based on their structure mGluRs selectively suppresses excitatory neurotransmission but and physiological activity, they have been divided into three does not have an effect on inhibitory neurotransmission [42].In groups: group I (mGluR1 and mGluR5), group II (mGluR2 and the rat globus pallidus [43] and substantia nigra pars reticulata mGluR3), and group III (mGluR4, mGluR6, mGluR7 and mGluR8). [44], activation of group III mGluRs inhibits both excitatory and The three groups of mGluRs are highly expressed in the neocortical inhibitory neurotransmission. In guinea pig hippocampal interneu- layers, hippocampus, basal ganglia, thalamus/hypothalamus, cere- rons, but not pyramidal neurons, activation of group III mGluRs by bellum and spinal cord; however, mGluR6 expression is restricted the selective group III mGluRs agonist L(+)-2-amino-4- to the visual sensory system in retinal rod bipolar cells [20]. phosphonobutyric acid (L-AP4) has been shown to suppress both Subcellularly, group I mGluRs are predominantly localized in post- excitatory and inhibitory neurotransmission. L-AP4 can also synaptic membrane terminals where they mainly activate Gq sig- enhance glutamate release in rat entorhinal cortex [45]. naling. Nevertheless, group I mGluRs have also been shown to be Conversely, it has been shown to reduce glutamate release in the localized in presynaptic terminals in the lamprey spinal cord substantia nigra [46]. This discrepancy may reflect where they promote neurotransmitter release and control motor -specific effects of the individual activated mGluRs in differ- function [21]. ent brain regions. Nevertheless, a better understanding of the com-

Activation of postsynaptic mGluR1s stimulated Gaq-mediated plexity mGluR function and signaling will require the development Ca2+ release from Ca2+ stores in the endoplasmic reticulum (ER) more selective agonists and antagonists for each individual mGluR. has been shown to lead to long-term depression (LTD) in cerebellar slices from rats and mice [22]. Further studies indicate that genetic 2.2. c-Aminobutyric acid B receptors (GABABRs) deletion of mGluR1 results in deficient cerebellar LTD and ataxia

[23]. Correlative evidence also suggests that the loss of Gq signal- GABA belongs to the first class of classical neurotransmitters ing, which involves reduced protein kinase C (PKC) and phospholi- and is the major inhibitory neurotransmitter in the CNS where it pase C-b-4 (PLCb4) activity and inositol 1,4,5 trisphosphate plays a crucial role in the control of excitability, plasticity, and net- 2+ (IP3)-mediated release of intracellular Ca ER stores from cerebel- work synchronization. GABA is produced in the presynaptic mem- lar Purkinje cells results in the ataxic behavior [24–28]. Given that brane terminals of GABAergic neurons from glutamine, which is cerebellar damage has been associated with the ataxia phenotype generated in astrocytes [47]. GABA mediates inhibitory neuro-

[29], these studies suggest that mGluR1-mediated LTD is crucial transmission through two types of GABA receptors, GABAA recep- for the maintenance of cerebellar function. tors (GABAARs) and GABABRs. Both GABAARs and GABABRs are Activation of the mGluR1s also generates slow excitatory post- widely distributed in the mammalian brain and are highly synaptic potentials (sEPSPs). This effect is mediated by the tran- expressed in cortical, hippocampal, thalamic, basal ganglia, and sient receptor potential channel 3 (TRPC3) [30], a non-selective cerebellar structures [48] and are involved in numerous functions, channel permeable to Ca2+, sodium (Na+) and other cations [31]. including epilepsy, schizophrenia, depression and anxiety [49–52].

A recent study indicates that the function of TRPC3 is dependent Subcellularly, both GABABR subtypes are localized to presynaptic on intracellular Ca2+ levels and is regulated by the stromal interac- and postsynaptic membrane terminals [53]. Specifically, the tion molecule 1 (STIM1) [32], which primarily localizes to ER mem- GABAARs, which are ionotropic receptors, function in chloride ion branes [33,34]. The putative link between TRPC3-mediated sEPSPs channel conductance and the induction of fast synaptic inhibition. and the ataxic phenotype in mGluR1 knockout (KO) mice remains Unlike GABAARs, GABABRs belong to the Rhodopsin GPCR family unclear. However, it has been reported that induction of LTD and mediate slow and prolonged inhibitory signals. There are 2+ requires a transient Ca elevation in [35], which could two subtypes of GABABRs, GABAB1Rs and GABAB2Rs, which are gen- 2+ be due to TRPC3-mediated Ca permeabilization, suggesting the erated from one gene by different promoters. A functional GABABR involvement of TRPC3 in the regulation of LTD. requires the formation of a GABAB1R and GABAB2R heterodimer In contrast to group I mGluRs, group II mGluRs are predomi- [54]. During receptor activation, GABA binds to the GABAB1R, nantly localized in presynaptic membrane terminals. Activation inducing heterodimerization with the GABAB2R and subsequent of presynaptic group II mGluRs with the selective group II mGluR GABAB2R-mediated activation of Gi/o proteins. Following activation 0 0 0 0 agonists LY354740 or (2S,2 R,3 R)-2-(2 ,3 -dicarboxycyclopropyl) of Gi/o,Gbc dimers are released and bind to and inhibit glycine (DCG-IV) has been reported to inhibit EPSCs [36,37] and voltage-dependent calcium channels (VDCCs) to suppress Ca2+ induce LTD [38]. Indeed, treatment with LY354740 induces influx. In addition, Gbc dimers directly interact with the anxiolytic-like behavior in mice as determined by the elevated plus C-terminus of the synaptosomal-associated protein 25 (SNAP25) maze behavioral paradigm [39]. In contrast, the anxiolytic-like to limit vesicle fusion, reduce GABA release, and negatively control activity is absent in mGluR2 and mGluR3 KO mice treated with GABAergic neurotransmission [55,56]. At postsynaptic terminals, 1610 Y. Huang, A. Thathiah / FEBS Letters 589 (2015) 1607–1619

GABABRs activate the G protein-coupled inwardly-rectifying potas- been shown to be involved the regulation of synaptic transmission sium (GIRK) channels, which generate a potassium (K+) ion influx and neuronal excitation through inhibition of K+ channels [68,69]. and hyperpolarization of the [57].Gbc dimers have Pharmacological studies using the non-selective mAChRs agonist been shown to bind to GIRK channels to mediate neuronal hyper- carbachol has been shown to induce long-term potentiation (LTP) polarization [58]. Numerous studies have also revealed that lipid of excitatory synaptic transmission in mouse hippocampal slices rafts, scaffold proteins, targeting motifs in the receptor, and regu- [70]. The effect is abolished in M1R KO mice [70], and in fact, these lators of G-protein signaling (RGS) proteins also contribute to the mice display a mild reduction in hippocampal LTP [71]. function of GABABRs. Collectively, this complex regulation of Interestingly, studies with the M1R KO mice suggest that the GABABRs in the brain may provide opportunities for novel strate- M1R is not necessary for hippocampus-dependent learning and gies to regulate GABA-dependent inhibition in normal and dis- [72]; however, M1R KO mice display an impairment in eased states of the CNS. working memory and consolidation in the win-shift radial arm

Generation of the GABAB1R and GABAB2R KO mice has provided and social discrimination behavioral paradigms [71]. These tests significant insight into the physiological function of these recep- evaluate hippocampal-dependent functions and are consistent tors. GABAB1R KO mice display behavioral abnormalities such as with changes in LTP determined by genetic and pharmacological epilepsy, hyperalgesia, impaired memory, increased anxiety and modulation of the M1R. Interestingly, M1R KO mice display a pro- decreased depression [59,60]. GABAB2R KO mice display similar nounced increase in locomotor activity [73], indicating an effect on behavioral deficits, including epilepsy, hyperalgesia and impaired the striatum, a region of the brain that is important for motor con- memory [61]. Nevertheless, anxiety and depression phenotypes trol [74]. In this regard, activation [75] or inhibition [76] of the have not been examined in the GABAB2R KO mice. The heteromeric M1R represent potential approaches in the treatment of nature of native GABABRs has been further emphasized by the sub- Alzheimer’s and Parkinson’s disease, respectively. stantial downregulation of GABAB1R protein in GABAB2R KO mice The M2Rs are predominantly expressed in thalamus, hypothala- [61]. An analogous requirement of GABAB1R for stable expression mus, midbrain, pons-medulla and cerebellum. The M4Rs are of GABAB2R was also observed in GABAB1R KO mice [60]. expressed in the cortex, corpus striatum, hippocampus, thalamus, Interestingly, the remaining GABAB1R protein in GABAB2R KO neu- hypothalamus, pons-medulla and cerebellum. Subcellularly, the rons accumulates in distinct cellular compartments in comparison M2R is expressed in the somatodendritic compartment, postsynap- to wild-type neurons, relocating from distal neuronal sites to the tic terminals, and presynaptic terminals in cholinergic neurons and proximal dendrites [61]. These studies suggest that the [77]. In striatal neurons, the M4R is preferentially expressed in association of the GABAB2R with the GABAB1R is essential for recep- the plasma membrane of perikarya and dendrites of medium spiny tor localization in distal processes but is probably not absolutely neurons [78]. Unlike the M1R, the M2R and M4R couple to Gi/o pro- necessary for signaling. Therefore, it is possible that functional teins to inhibit neuronal excitation. The M2R and M4R are localized

GABAB1Rs exist in neurons that naturally lack GABAB2R subunits; to both presynaptic and postsynaptic terminals. M4R, but not M2R, however, heteromeric GABAB1/2Rs are the prevalent GABABRs in KO mice show increased basal ACh release in the hippocampus. the CNS and the majority of GABAB2R protein is normally associ- ACh release is further elevated in M2R and M4R double KO mice ated with the GABAB1R. relative to M4R KO mice alone [79]. These studies were confirmed with the non-selective scopolamine and the 2.3. Muscarinic acetylcholine receptors (mAChRs) M2/M4 antagonist AF-DX384, which induce ACh release in the hip- pocampus [80]. Interestingly, the antagonist-induced ACh release Acetylcholine (ACh) belongs to the first class of classical neuro- can be attenuated by M2R antisense treatment or in M2R KO mice transmitters and is involved in the modulation of various brain but not with M4 antisense treatment or in M4R KO mice [79,80]. functions. In cholinergic neurons, choline acetyltransferase Given that the M2Rs, but not the M4Rs, are highly expressed in (ChAT) transfers an acetyl group from acetyl coenzyme A to choline hippocampus, these results suggest that low expression of the which results in the generation of ACh [62]. The newly synthesized M4Rs in the hippocampus may interfere with the M2R modulation ACh is then transported into vesicles by the vesicular ACh trans- of basal ACh levels. Conversely, the M2R may predominantly inhi- porter (VAChT). Release of ACh activates two types of receptors: bit ACh release in the hippocampus and cerebral cortex while the muscarinic ACh receptors (mAChRs) and nicotinic ACh receptors M4R mediates ACh release in the striatum [81]. The (nAChRs). MAChRs are GPCRs while nAChRs are ligand-gated M2R-mediated neurotransmitter release is modulated by Gbc 2+ cation channels. In the current review, we will focus the discussion dimers released from Gi/o proteins, which inhibit N-type Ca chan- on the function of the mAChRs in neurotransmission. nels and Ca2+ influx [57]. The M2R-mediated neurotransmitter There are five subtypes of the mAChR family, the muscarinic release is also dependent on the voltage-sensitive function of the acetylcholine receptors 1–5 (M1R–M5R). Most mAChRs, except M2R (see Section 3 for further discussion). Postsynaptically, activa- the M5Rs, are differentially expressed in various brain regions tion of the M2Rs by ACh has been shown to inhibit EPSPs in CA1

[63]. The M1Rs are highly expressed in the cerebral cortex, hip- pyramidal cells through the activation of Gi/o protein signaling pocampus and corpus striatum and are predominantly localized and GIRK channels [82]; however, there is lack of evidence to to brain regions that regulate . In the cortex, demonstrate the function of postsynaptic M4Rs during the M1R is localized in layers II–VI of the cortex [64]. In the hip- neurotransmission. pocampus, the M1R is expressed in the CA1 and The M3Rs are expressed at relatively low levels in the cortex, [65]. In the striatum, the M1R is found in the perikarya and in med- corpus striatum, hippocampus, thalamus, hypothalamus, midbrain, ium spiny neurons [66]. In neurons, the M1R is expressed in both and pons-medulla. The M3R is expressed in presynaptic membrane presynaptic and postsynaptic membrane terminals [65]. The M1R terminals, somata and postsynaptic membrane terminals [64]. The preferentially couples to the G protein Gaq, resulting in increase role of the M3Rs in neurotransmission is largely unknown. Given in intracellular Ca2+ levels, which facilitates presynaptic ACh that the M3R is the major mAChR involved in smooth muscle con- release. In contrast, inhibition of presynaptic M1Rs with an traction, the M3R KO mice display stomach fundus, urinary blad- M1R-selective antagonist reduces ACh release from presynaptic der, and trachea problems [83]. As a result of the anatomical terminals [67]. Activation of postsynaptic M1Rs by ACh elevates distribution of the M3R receptor in presynaptic and postsynaptic intracellular Ca2+ levels and leads to slow postsynaptic depolariza- membrane terminals, a functional role for the M3Rs in neurotrans- tion and an increase in neuronal excitability. The M1R has also mission cannot be excluded; however, given the absence of a Y. Huang, A. Thathiah / FEBS Letters 589 (2015) 1607–1619 1611 brain-specific phenotype in the M3R KO mice, the studies to date These in vivo findings are especially intriguing in light of findings suggests a possible redundancy of M3R function with other that LTP is impaired in neostriatal slices from A2AR KO mice mAChRs. [110]. These results are consistent with the observation that brain-derived neurotrophic factor (BDNF) levels, which has been 2.4. Adenosine receptors (ARs) shown to induce LTP [111], are reduced in the hippocampus of

A2AR KO mice [112]. Interestingly, studies have also shown that Adenosine is a purine nucleoside, which is essential in nucleic the A1Rs and A2ARs form heterodimers that are involved in modu- acid and ATP synthesis. In peripheral tissues, adenosine can be lation neurotransmission with stimulation of the A2ARs leading to a released in response to various stress-related conditions including decrease in agonist affinity for the A1Rs [113]. Although the A2BRs inflammation, hypoxia, and tissue damage [84,85]. Although ade- are expressed at low levels in comparison to the A2AR in the hip- nosine is not a neurotransmitter, adenosine acts as a neuromodu- pocampus, this receptor has also been shown to regulate lator in the CNS to regulate neuronal excitability and the release of A1R-mediated inhibition of synaptic transmission [114]. a wide range of neurotransmitters including glutamate, GABA, The A3Rs are highly expressed in peripheral tissues with a very acetylcholine and dopamine [86]. The effects of adenosine are low expression throughout the brain [91]. Although the A3Rs cou- mediated by the adenosine receptors (ARs), A1R, A2AR, A2BR and ple to Gi/o proteins and are present in both presynaptic and postsy- A3R, which all belong to the GPCR family. naptic terminals, the role of A3Rs in synaptic transmission remains The A1Rs are highly expressed in the brain in the cortex, hip- to be elucidated. Studies utilizing a non-selective agonist, 2-chlor pocampus, and cerebellum, specifically in neurons and , includ- o-N6-(3-iodobenzyl)-adenosine-50-N-methyluronamide ing microglia and astrocytes [87]. In hippocampal neurons, the (CI-IB-MECA) [86], which also binds to A1Rs, has not provided con- A1Rs are expressed in both presynaptic and postsynaptic mem- clusive evidence for the functional role of the A3Rs in neurotrans- brane terminals [88]. The A1Rs couple to Gi/o proteins to regulate mission. Nevertheless, recent studies with A3R KO hippocampal inhibitory synaptic transmission [89]. Activation of presynaptic brain slices and the selective A3R antagonist MRS1523 indicate that Gai/o-coupled A1Rs negatively regulates activity, the chemokine fractalkine (CX3CL1) inhibits hippocampal LTP cAMP accumulation and activation of (PKA), through A3R activity [115,116], suggesting a putative role for the which leads to an induction of LTD [90]. Concurrently, the released A3R in the modulation of synaptic activity. Collectively, these stud- Gbc dimers inhibit P/Q-type and N-type Ca2+ channels and reduce ies suggest that regulation of synaptic neurotransmission by the presynaptic Ca2+ influx [91], which results in a reduction in gluta- ARs is extremely complex and involves an exquisite fine tuning mate release in presynaptic terminals, glutamate-mediated NMDA of the activation and/or inhibition of AR subtypes. activation in postsynaptic terminals and EPSCs [92,93]. Stimulation of postsynaptic A1Rs has been shown to result in Gbc dimer bind- 2.5. 5-Hydroxytryptamine receptors (5-HTRs) ing to and activation of GIRK channels, which leads to a reduction in excitation in postsynaptic terminals [57,58,94]. In contrast, elec- Serotonin or 5-HT is a monoamine neurotransmitter, which reg- trophysiology studies conducted in hippocampal slices indicate ulates various physiological functions. In the brain, serotonin is that A1R KO mice display normal LTP and LTD, but exhibit a drastic produced in neurons which are mainly localized to reduction in paired pulse facilitation [72], suggesting an essential the raphe nuclei in the midline of the brainstem [117]. role of the A1R in the presynaptic terminal and short-term synaptic Serotonergic neurons project to various brain regions including plasticity. Consistent with the observations on LTP and LTD, the the cortex, hippocampus, midbrain and hindbrain, generating in

A1R KO mice show normal learning and memory in Morris water a vast serotonin network throughout the brain. Accordingly, the maze behavioral paradigm [72,95]; however, these mice display serotonin network modulates numerous and widespread physio- hyperalgesia, anxiety and emotional instability [95–97]. Further logical functions including perception, motor control, memory, investigation is required to understand whether these phenotypes aggression, , and fear [117]. The regulation of serotonin are due to a presynaptic or postsynaptic defect in the absence of signaling is mediated by 14 serotonin receptors (Table 1), which the A1R. are classified into 7 families, 5-HT1-7 receptor (5-HT1-7R). Most of The A2ARs are mainly expressed in the striatum with lower the 5-HTRs are GPCRs with the exception of the 5-HT3Rs, which levels of expression observed in the cortex and hippocampus are ligand-gated cation channels. In neurons, the 5-HTRs are

[98]. Specifically, the A2ARs are highly expressed in postsynaptic mainly localized in postsynaptic terminals; however, some terminals in striatal neurons and presynaptic terminals in hip- 5-HTRs, such as 5-HT1AR, 5-HT2AR and 5-HT4R, are also expressed pocampal neurons [99]. In contrast, the A2BRs are highly expressed in presynaptic terminals [118]. Consequently, individual neurons in peripheral tissues with a very low expression levels throughout may express multiple 5-HTRs with differential effects on neuro- the brain [98]. Unlike the A1R, the A2ARs couple to Gs proteins, and transmission. For example, layer V pyramidal neurons express the A2BRs couple to both Gs and Gq. Activation of the A2ARs or A2BRs 5-HT1ARs and 5-HT2ARs, which exert opposing effects on pyramidal leads to an increase in cAMP accumulation and the activation of neuron firing [119]. CNS serotonergic neurons are well-positioned PKA and PKC, respectively, resulting in the facilitation of neuro- to modulate the activity of a wide variety of circuits, transmission [100,101]. Stimulation of the A2ARs leads to an which partially explains the pleiotropic behavioral effects of sero- increase glutamate release from presynaptic terminals [102], tonin [120]. A full discussion on the modulation of serotonergic which could be due to the activation of Gas-orGaq-dependent sig- neurotransmission has been nicely reviewed elsewhere [121] and naling cascades [100,101]. The released glutamate then binds to has been summarized in Table 1. In this section, we will focus postsynaptic NMDA receptors (NMDARs) to promote postsynaptic the discussion on the role of the 5-HT1AR in neurotransmission. excitation and LTP [103,104]. The A2AR specific agonist CGS 21680 Administration of 5-HT1ARs selective agonists has been shown has been shown to facilitate synaptic neurotransmission through to disrupt memory function in mice [122] and humans [123].In

PKA and PKC in hippocampal slices [105]. Conversely, acute treat- contrast, the selective 5-HT1ARs antagonist, WAY-100635, has been ment of rats hippocampal slices with the A2AR selective antagonist shown to prevent the cognitive deficits induced by, not only SCH 58261 or chronic treatment of rats with the A2AR selective 5-HT1AR stimulation but also by cholinergic or NMDAR blockade antagonist KW-6002 inhibits LTP [106,107]. In contrast to the [124]. Adminstration of the same 5-HT1AR antagonist attenuates pharmacological studies, A2AR KO mice display an improvement LTP in rat brains by in vivo electrophysiological recordings [125]. in spatial recognition memory [108] and working memory [109]. Conversely, induction of LTP is inhibited by the 5-HT1AR selective 1612 Y. Huang, A. Thathiah / FEBS Letters 589 (2015) 1607–1619

Table 1 Neuronal GPCRs.

Family GPCR G protein Synaptic localization Synaptic function after Reference(s) activation

Metabotropic glutamate mGluRl Gq Presynaptic and postsynaptic terminals Excitatory [21,198] receptors (Group I) mGluR5

Metabotropic glutamate mGluR2 Gi/o Presynaptic terminal Excitatory or inhibitory [36–38,41,198] receptors (Group II) mGluR3

Metabotropic glutamate mGluR4 Gi/o Presynaptic terminal Excitatory or inhibitory [42–46,198] receptors (Group III) mGluR6 Postsynaptic terminal mGluR7 Presynaptic terminal mGluR8 Presynaptic terminal

GABAB receptors GABAB1R Gi/o Presynaptic and postsynaptic terminals Excitatory or inhibitory [199]

GABAB2R

Muscarinic acetylcholine M1R Gq Presynaptic and postsynaptic terminals Excitatory [64–70,200,201]

receptors M2R Gi/o Presynaptic and postsynaptic terminals Inhibitory [77,79–82]

M3R Gq Presynaptic and postsynaptic terminals N.I. [64]

M4R Gi/o Presynaptic and postsynaptic terminals Inhibitory [78–81]

M5R Gq N.I. N.I. [202]

Adenosine receptors A1RGi/o Presynaptic and postsynaptic terminals Inhibitory [87,92]

A2ARGs Presynaptic and postsynaptic terminals Excitatory [87,102,113,203,204]

A2BRGs,Gq Presynaptic terminal Excitatory [87,114]

A3RGi/o Presynaptic and postsynaptic terminals N.I. [87]

5-HT receptors 5-HT1ARGi/o Presynaptic and postsynaptic terminals Inhibitory [118,121]

5-HT1BR Presynaptic and postsynaptic terminals [118,121]

5-HT1DR Presynaptic and postsynaptic terminals [118,121]

5-HT1ER Postsynaptic terminal [118,121]

5-HT1FR Presynaptic and postsynaptic terminals [118,121]

5-HT2ARGq Presynaptic and postsynaptic terminals Excitatory [118,121]

5-HT2BR [118,121]

5-HT2CR [118,121]

5-HT4RGs Presynaptic and postsynaptic terminals Excitatory [118,121]

5-HT5ARGi/o Postsynaptic terminal Inhibitory [118,121]

5-HT5BR [118,121]

5-HT6RGs Postsynaptic terminal Excitatory [118,121]

5-HT7RGs Postsynaptic terminal Inhibitory [118,121]

Neuropeptide Y receptors NPY1RGi/o Postsynaptic terminal Inhibitory [136,138]

NPY2RGi/o Presynaptic terminal Inhibitory [136,141]

NPY4RGi/o N.I. N.I. [136]

NPY5RGi/o Postsynaptic terminal Inhibitory [136,205]

Cannabinoid receptors CB1RGi/o Presynaptic and postsynaptic terminals Inhibitory [152,155,156,161]

CB2RGi/o Presynaptic and postsynaptic terminals N.I. [153]

N.I.: no information.

agonist 8-OH-DPAT, and the effect is blocked following treatment 2.6. Y receptors (NPYRs) with 5-HT1AR antagonists [126,127]. The 5-HT1AR couples to Gi/o proteins, resulting in the activation of Gai/o signaling and The Neuropeptide Y (NPY) belongs to the pancreatic polypep- decreased cAMP accumulation and PKA activity [128]. tide family which includes two additional family members: pep- Concurrently, the released Gbc dimers activate GIRK channels, tide YY (PYY) and pancreatic polypeptide (PP) [135]. NPY is which results in hyperpolarization and inhibition of postsynaptic synthesized in the ER as a large precursor protein. Following a potentials [128–130]. The 5-HT1AR has also been shown to block series of post-translational modifications and enzymatic cleav- N-type and P-type Ca2+ channels, reducing Ca2+ influx through ages, a 36 amino acid NPY is exocytosed into the extracellular

Gi/o signaling via Gbc dimers [131,132]. At the synapse, activation space [136]. NPY is one of the most abundant peptides in the of the 5-HT1ARs has been shown to inhibit NMDAR- and AMPA brain and is concentrated within the hypothalamic arcuate receptor (AMPAR)-mediated postsynaptic currents in prefrontal nucleus, brainstem, and anterior pituitary. It has been reported cortical pyramidal neurons [133,134]. This effect has been reported to modulate the stress response [136]. NPY is also abundantly to involve the inhibition of Ca2+/calmodulin-dependent kinase II expressed in the dentate gyrus where it modulates hippocampal

(CaMKII) activity through 5-HT1AR-stimulated Gi/o protein signal- excitability. ing. Specifically, stimulation of Gi/o signaling suppresses Four NPY receptors NPY1R, NPY2R, NPY4R, and NPY5R have been PKA-mediated CaMKII activation and the activation of identified in humans. The NPY1R, NPY2R, and NPY5R are activated mitogen-activated protein kinase kinase/extracellular by NPY and PYY, whereas the NPY4R is activated by PP [136]. All signal-regulated kinase (MEK/ERK) signaling cascades, which regu- four NPYRs are expressed in the brain. The NPY1R and NPY2R are late the microtubule/kinesin-based transport of NMDARs to den- expressed at higher levels in the brain relative to NPY4R and drites and AMPAR activation [133,134]. Collectively, the evidence NPY5R. The hippocampus is particularly enriched in NPY and the indicates that 5-HT1ARs impair memory function through activa- NPY1Rs and NPY2Rs. [137]. The NPYRs are a family of tion of both Ga and Gbc signaling and several downstream Gi/o-coupled GPCRs, while NPY2Rs also interact with Gq. NPY1Rs effectors. and NPY2Rs play an important role in the modulation of glutamate Y. Huang, A. Thathiah / FEBS Letters 589 (2015) 1607–1619 1613 release in the CA3 and dentate gyrus [138]. Selective activation of abundant GPCR in the brain. It is widely distributed in the cortex, 2+ both receptors has been shown to inhibit intracellular Ca and hippocampus, cerebellum, and basal ganglia [152]. The CB2R is pre- glutamate release in hippocampal presynaptic terminals [138]. dominantly expressed in peripheral tissues, but it is also expressed This effect may be due to modulation of K+ and Ca2+ channels in in the cortex, hippocampus, midbrain and cerebellum [153]. Both the presynaptic terminal [139,140]. Consistent with these findings, the CB1R and CB2R are expressed in neurons and glia cells. In neu- 2+ NPY2R activation has been reported to inhibit multiple Ca chan- rons, both receptors are present in the soma, dendrites, and in axon nels including N-type, P/Q-type, and presynaptic VDCCs, leading to terminals. Both the CB1Rs and CB2Rs primarily couple to Gi/o pro- a reduction in intracellular Ca2+ levels and glutamate release teins, which leads to the inhibition of adenylyl cyclase and a reduc-

[138,141]. Given that NPY1Rs and NPY2Rs function in the inhibition tion in cAMP levels. Activation of CB1Rs, but not CB2Rs, also results of glutamatergic neurotransmission, the absence of these receptors in the inhibition of various VDCCs and the activation of GIRK chan- may lead to an improvement in cognitive function. Currently, one nels [154]. The CB1R/CB2R agonist WIN 55,212-2 inhibits EPSCs in report indicates that NPY1R KO mice display a late extinction in hippocampal slices [155]. This effect can be partially blocked by a fear conditioning, suggesting a role for the NPY1R in memory con- selective CB1R antagonist AM251 and in CB1R KO hippocampal solidation [142]. However, behavioral studies indicate that the slices [155]. These results suggest that the CB1R is involved in NPY2R KO mice display learning and memory deficits in the the inhibition of EPSCs whereas the role of the CB2R remains to Morris water maze [143] and object recognition behavioral para- be defined. digms [144]. These findings potentially reflect the fact that the The presynaptic and postsynaptic localization of the CB1Rs sug- NPY2Rs also depress GABAergic neurotransmission [145]. gests that these receptors are involved in the regulation of both Alternatively, the NPY1R may partially functionally compensate presynaptic and postsynaptic activity. It is well-documented that for the absence of the NPY2R in the NPY2R KO mice. Indeed, a activated presynaptic CB1Rs inhibit the release of several neuro- recent study indicates that NPY1R/NPY2R double KO mice exhibit transmitters, including glutamate, GABA, and dopamine [156]. a strong fear conditioning phenotype, which is not observed in The NMDARs, at postsynaptic terminals, have been reported to 2+ the individual NPY1R or NPY2R KO mouse models [142]. This evi- bind to glutamate to generate a Ca influx, which is crucial for dence suggests that the NPY1R may functionally compensate for postsynaptic excitation [157]. Various studies have also demon- the absence of the NPY2R and vice versa. Interestingly, conditional strated NMDAR-mediated EPSCs [158–160]. Interestingly, the inactivation of the NPY1R in NPY5R-expressing neurons in mice CB1R has been shown to directly interact with the NMDAR NR1 leads to an increase in anxiety-related behaviors and an improve- subunit [161], which, in turn, promotes the internalization of both ment in spatial reference memory [146]. Both the NPY1Rs and the CB1R and NR1 subunit, resulting in a reduction in the NMDAR NPY5Rs have been reported to mediate the NPY-induced at the cell surface and the inhibition of EPSCs [161,162]. These anxiolytic-like activity in the elevated plus maze and open field studies suggest that the CB1R modulates NMDAR-mediated tests [147]; however, NPY5R KO mice display normal function in EPSCs. Further studies will be required to determine whether G the elevated plus maze and open field tests [148], suggesting that protein signaling or additional effector molecules are involved in the NPY1R is primarily responsible for the anxiolytic-like pheno- the observed effect. type [149]. The NPY5R has also been reported to increase sponta- Several studies indicate that the CB1Rs reduce excitatory neu- neous GABA release from GABAergic neurons, resulting in an rotransmission by modulating both presynaptic and postsynaptic induction of inhibitory synaptic transmission [150]. NPY5RKO activities [163–165], suggesting a putative effect on learning and mice exhibit normal learning and memory in the Morris water memory. In this regard, several CB1R agonists, including maze and object recognition tests [148]. These results suggest that A(9)-tetrahydrocannabinol (THC), CP55,940 and WIN55,212-2, the NPY5R display functional redundancy with other NPYRs. have been shown to impair learning and memory in the The NPY4R KO mice exhibit reduced anxiety-like and eight-arm radial maze, Morris water maze, and T-maze behav- depression-related behavioral phenotypes, similar to NPY2RKO ioral paradigms [166–169]. In addition, CB1Rs KO mice display mice [144] and in contrast to NPY1R KO mice. A role for the enhanced learning and memory function in active avoidance NPY4R in neurotransmission has not been reported; however, these [170] and object recognition behavioral tests [171]. Both para- studies suggest that NPY4R may also be involved in the regulation digms evaluate hippocampal-dependent cognitive function, of neurotransmission. which suggests that the CB1Rs may modulate glutamatergic neu- The large number of Y receptors has made it difficult to delin- rotransmission and EPSCs in vivo. The CB2Rs are less abundant in eate their individual contributions in physiological processes. the brain relative to CB1Rs. The CB2R KO mice display a Although recent studies with KO mouse models have begun to schizophrenia-like phenotype [172], which supports a role for unravel the functions of these receptors, the use of conditional this receptor in the modulation of neuronal excitation; however,

KO models has facilitated determination of the specific function the function of CB2Rs in neurotransmission requires further of the individual receptor subtypes in distinct regions of the brain investigation. and should yield further insight into the biological regulation of these receptors. 3. Autoreceptors 2.7. receptors (CBRs) Several GPCRs are localized in both presynaptic and postsynap- The endocannabinoids are a group of neurotransmitters which tic membrane terminals where they are involved in the regulation are generated from the degradation of membrane of neurotransmitter release. Interestingly, presynaptic GPCRs also [151]. Amongst the various identified endocannabinoids, function as autoreceptors. Autoreceptors are activated by the same N-arachidonoylethanolamine (AEA) and 2-arachidonoylglycerol type of neurotransmitter released from the nerve terminal [173]. (2-AG) are the major endocannabinoids. They are the physiological Consequently, autoreceptors regulate the intrasynaptic feedback ligands for two GPCR cannabinoid receptors: cannabinoid receptor of released neurotransmitters and modulate neurotransmission

1 (CB1R) and cannabinoid receptor 2 (CB2R). Endocannabinoids act between neighboring synapses. A variety of GPCRs have been through the CB1R and the CB2R to regulate a variety of physiolog- reported to function as autoreceptors. For example, 5-HT1A autore- ical functions in the CNS and peripheral tissues. The CB1Ris ceptors negatively regulate the release of 5-HT from serotonergic expressed in the brain and peripheral tissues and is the most neurons in dorsal raphe nuclei [174]. This effect has been reported 1614 Y. Huang, A. Thathiah / FEBS Letters 589 (2015) 1607–1619

to be due to the activation of 5-HT1AR-mediated inhibitory Gi/o pro- Table 2 tein signaling, thereby inhibiting the firing and activity of the tar- Astrocytic GPCRs. get neurons [175]. Family GPCR G Neurotransmission Reference(s) Group II and III mGluRs are predominantly localized in presy- protein function after naptic terminals and have also been shown to function as autore- activation ceptors, regulating inhibitory synaptic transmission. The selective Metabotropic mGluR3 Gi/o N.I. [206] group II mGluR agonists DCG-IV and 2R,4R-4-aminopyrrolidin glutamate mGluR5 Gq Glutamate release [188,191] receptors e-2,4-dicarboxylate (APDC) reduce neurotransmission in medial perforant path synapses, but not lateral perforant path synapses P2Y receptor P2Y1RGq Glutamate release [186,187] Protease- PAR1 G and Glutamate release [185] [176], which suggests that group II mGluR autoreceptor function q activated Gi/o may be synapse specific; however, due to lack of specific mGluR2 receptor and mGluR3 agonists, functional crosstalk between the receptors, GABABR GABABRGi/o Glutamate uptake [185] in the absence of autoreceptor activation, cannot be ruled out. Adenosine A1RGi/o Glutamate release [185,197] Subcellular distribution of the group III mGluR mGluR7 suggests receptors A2ARGs GABA uptake [197] that it may also function as an autoreceptor [177]; however, Cannabinoid CB1RGi/o Glutamate release [185] mGluR subtype-specific agonists would be required to definitely receptors CB2RGi/o N.I. [207] elucidate the potential role as mGluR7 autoreceptors. Adrenergic a1AAR Gq Glutamate uptake [208,209] receptors a2AAR Gi/o N.I. [208,209] Presynaptic GABABRs have also been reported to display autore- b2AR Gs and GABA uptake? [208,209] ceptor function. Activation of GABABRs by the selective agonist G Decrease in glutamate 2+ i/o baclofen has been shown to induce presynaptic Ca currents uptake? [178], which results in a suppression of GABA release in neurons Dopamine D2RGi/o N.I. [210,211] of the suprachiasmatic nucleus caused by inhibition of P/Q-type receptors Ca2+ channels via Gbc dimers [178,179]. These studies confirm N.I.: no information. the autoreceptor function of GABABRs, which negatively regulate GABA release. Electrophysiological studies in GABAB2R KO mice have shown that the GABABR autoreceptor function is completely abolished [61], indicating the GABA binding to the remaining GPCR activation and G protein-signaling are involved in the regu-

GABAB1Rs in GABAB2R KO mice is not sufficient to preserve autore- lation of slow and fast glutamate release from astrocytes [185]. ceptor function. These studies demonstrate that a functional Specifically, the protease-activated receptor 1 (PAR1), a GPCR autoreceptor requires G-protein signaling to regulate neurotrans- which is expressed in most CA1 hippocampal astrocytes, but not mitter release. in CA1 pyramidal neurons, couples to two G proteins, Gi/o and Gq. Interestingly, M2Rs, mGlu3Rs, and GABABRs exert a tonic inhi- Selective agonist stimulation of the PAR1 activates both G bitory effect on neurotransmitter release, probably via direct protein-signaling cascades, inducing both fast and slow glutamate actions on the exocytotic machinery [180]. Depolarization has release. Conversely, blocking the Gi/o pathway with PTX abolishes been suggested to inhibit all three of these receptors [180], which fast, but not slow, glutamate release [185], suggesting that should lead to enhanced neurotransmitter release. Evidence in Gi/o-coupling is required for fast glutamate release in astrocytes. support of this hypothesis has recently been obtained from studies Further studies indicate that several other Gi/o-coupled GPCRs, of neurotransmitter release in which pertussis toxin (PTX)-induced including GABABRs, A1Rs, and CB1Rs, stimulate fast astrocytic glu- uncoupling of inhibitory autoreceptors from their G proteins exerts tamate release, opening the glutamate-permeable, two-pore effects independently of changes in Ca2+ release [181]. domain potassium channel TREK-1 [185].

Theoretically, this direct voltage control of synaptic function could PAR1-activated Gq signaling appears to mediate slow glutamate contribute to synaptic plasticity [180]. Accordingly, M2R-deficient release, is Ca2+-dependent, and requires the opening of the mice show behavioral and memory deficits and major changes in glutamate-permeable, Ca2+-activated anion channel Best1 [185]. synaptic plasticity at the cellular level [182]; however, the rele- In contrast, stimulation of the purinergic P2Y1 receptor (P2Y1R), vance of the M2R voltage dependence in these mice remains to another Gq-coupled GPCR, with the non-selective agonist be ascertained. ADP-analogue 2-methylthioadenosine-50-diphosphate (2MeSADP) was observed to induce fast glutamate release from astrocytes in 4. Astrocytic GPCRs hippocampus [186,187]. Group I mGluRs (mGluR1 and mGluR5) are also Gq-coupled GPCRs which are expressed in astrocytes It is well-documented that astrocytes are involved in the mod- [188]. Stimulation of group I of mGluRs with a non-selective ago- ulation of synaptic activity. Astrocytes play a pivotal role in the nist, (S)-3,5-dihydroxyphenylglycine (DHPG), evokes fast gluta- synthesis of the precursor glutamine for the biosynthesis of the mate release from astrocytes via exocytosis of glutamate two major excitatory and inhibitory neurotransmitters: glutamate [189,190]. However, application of 2-methyl-6-(phenylethy and GABA [183]. Glutamine is released from astrocytes through nyl)-pyridine (MPEP), a specific antagonist selective for mGluR5 SN1 transporters and transferred to presynaptic terminals of gluta- reduces glutamate release, suggesting that mGluR5 may modulate matergic and GABAergic neurons, where it is further processed into glutamate release in astrocytes [191]. Both 2MeSADP and DHPG 2+ glutamate and GABA. Glutamine can also be converted into gluta- have been reported to induce fast Ca influx, probably through 2+ 2+ mate and directly released from astrocytes. The release of gluta- VDCCs, and Gq-mediated slow Ca release from intracellular Ca 2+ mate from astrocytes has been shown to be regulated by a stores [192,193]. Collectively, these studies suggest that Ca influx 2+ 2+ variety of mechanisms including Ca -dependent vesicular exocy- may mediate fast glutamate release, whereas the Gq-mediated Ca tosis, purinergic P2X7 ion channels, gap junctions, anion channels, mobilization directs slow glutamate release. The group II mGluR reverse transport and cystine-glutamate antiporters [184]. mGluR3, which couples to Gi/o, has also been reported to be Astrocytes express a variety of GPCRs which are involved in the expressed in astrocytes; however, no study to date has reported regulation of synaptic activity (for a complete list of astrocytic the involvement of mGluR3 in glutamate release from astrocytes. GPCRs, see Table 2). In fact, a recent study indicates that astrocytic Collectively, these studies indicate that Gi/o and Gq-coupled Y. Huang, A. Thathiah / FEBS Letters 589 (2015) 1607–1619 1615 astrocytic GPCRs play a crucial role in the regulation of glutamate Acknowledgements release. Astrocytes are also involved control of neurotransmitter uptake This work was supported by the MNIRG from the Alzheimer’s from the extracellular space during neurotransmission, thereby Association, by the Fund for Scientific Research Flanders, the regulating neurotransmitter concentrations in the synaptic cleft University of Leuven (KUL), a Methusalem grant from the and the strength and duration of synaptic communication. In the University of Leuven (KUL) and the Flemish government, IWT case of the modulation of excitatory neurotransmitter release, agency for innovation by science and technology, and the although some synaptically released glutamate can be taken up Interuniversity Attraction Poles Program of the Belgian Federal by presynaptic or postsynaptic neuronal transporters or diffuses Science Policy Office. away from the synapse, the vast majority of glutamate uptake is carried out by astrocytic Na+-dependent glutamate transporters References [194]. 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