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Mini Review ARTICLE

Front. Cell. Neurosci., 10 April 2015 | https://doi.org/10.3389/fncel.2015.00135

Cross-talk and regulation between glutamate and GABAB receptors

  • Bradford School of Pharmacy, School of Life Sciences, University of Bradford, Bradford, West Yorkshire, UK

Brain function depends on co-ordinated transmission of signals from both excitatory and inhibitory neurotransmitters acting upon target neurons. NMDA, AMPA and mGluR receptors are the major subclasses of glutamate receptors that are involved in excitatory transmission at synapses, mechanisms of activity dependent synaptic plasticity, brain development and many neurological diseases. In addition to canonical role of regulating presynaptic release and activating postsynaptic potassium channels, GABAB receptors also regulate glutamate receptors. There is increasing evidence that metabotropic GABAB receptors are now known to play an important role in modulating the excitability of circuits throughout the brain by directly influencing different types of postsynaptic glutamate receptors. Specifically, GABAB receptors affect the expression, activity and signaling of glutamate receptors under physiological and pathological conditions. Conversely, NMDA receptor activity differentially regulates GABAB receptor subunit expression, signaling and function. In this review I will describe how GABAB receptor activity influence glutamate receptor function and vice versa. Such a modulation has widespread implications for the control of neurotransmission, calcium-dependent neuronal function, pain pathways and in various psychiatric and neurodegenerative diseases.

Introduction

Most excitatory signals that a neuron receives are mediated via glutamate receptors whereas most inhibitory signals are mediated via γ-aminobutyric acid (GABA) receptors (Cherubini et al., 1991; Hollmann and Heinemann, 1994). Many factors influence the regulation of excitatory and inhibitory synaptic inputs on a given neuron. One important factor is the subtype of neurotransmitter receptors present at not only the correct location to receive the appropriate signals but also their abundance at synapses (Dingledine et al., 1999; Sheng and Kim, 2011). Thus the molecular mechanisms that regulate receptor expression and localization at specific sites are of considerable importance. This review will describe the recent advances in our understanding of the molecular mechanisms underlying glutamate and GABAB receptors cross-talk and discuss the roles of specific proteins that might control these processes.

Glutamate receptors are the major excitatory neurotransmitter receptors in the brain and play an important role in neural plasticity and development. Improper function of glutamate receptors is involved in various psychiatric and neurodegenerative diseases (Mattson, 2008; Musazzi et al., 2013). N-methyl-D-aspartate receptors (NMDARs), α-amino-3-hydroxy-5-methyl-4-isoxazolepropionate receptors (AMPARs) and kainate receptors are glutamate-gated ion channels, whereas metabotropic glutamate receptors (mGluRs) are G-protein-coupled receptors (GPCRs) that signal downstream via interaction with heterotrimeric G-proteins. Pharmacological and molecular biological studies have revealed that glutamate receptors exist as different subclasses, where receptor subtypes comprise multiple subunits such as NMDA receptors (GluN1 to GluN3), AMPA receptors (GluA1 to GluA4), kainate receptors (GluK1 to GluK5) and mGlu receptors (mGluR1 to mGluR8) (for reviews, see Nakanishi et al., 1998; Lodge, 2009; Nicoletti et al., 2011).

Conversely, GABA receptors are the primary proteins responsible for inhibitory responses in the brain. Metabotropic GABA receptors (GABABRs) are GPCRs that can mediate slow inhibitory neurotransmission in the CNS. GABABRs are located at both presynaptic and postsynaptic compartments and changes in their number, localization and activity affect the level of synaptic inhibition. Presynaptic GABABRs inhibit release of neurotransmitter by inhibiting Ca2+ channels (Wu and Saggau, 1995; Takahashi et al., 1998). Activation of postsynaptic GABABRs activates inwardly rectifying K+ channels (GIRK) to generate slow inhibitory postsynaptic potentials (reviewed in Marshall et al., 1999; Bowery et al., 2002; Gainetdinov et al., 2004). The GABABR is a heteromeric GPCR consisting of GABAB1 and GABAB2 subunits that exert much longer lasting synaptic inhibition compared to GABAA ion channels (Marshall et al., 1999; Watanabe et al., 2002). The ligand-binding domain (Malitschek et al., 1999) is present in GABAB1 subunit and G-proteins interact with GABAB2 to regulate adenylate cyclase, GIRK channels and Ca2+ channels (Robbins et al., 2001). A large body of work over the last 20 years has demonstrated that GABAB receptors are regulated via mechanisms distinct from those utilized by many classical GPCRs such as the β2-adrenergic receptor (Bettler and Tiao, 2006). For example, following agonist exposure most GPCRs are phosphorylated and endocytosed from the cell surface into intracellular compartments and then either down-regulated via lysosomal or proteasomal degradation or recycled back to the cell surface following agonist removal. In contrast, cell surface GABAB receptor levels are not significantly altered upon receptor stimulation in cultured cortical and hippocampal neurons (Fairfax et al., 2004; Bettler and Tiao, 2006). GABAB receptors are very stable at the plasma membrane even after agonist exposure with little internalization in cultured neurons. The absence of receptor endocytosis correlates with lack of arrestin recruitment and agonist-induced phosphorylation (Fairfax et al., 2004). Surprisingly, increased phosphorylation at serine 892 in GABAB2 subunit decreased degradation rates and stabilizes surface GABABRs in neurons (Couve et al., 2004; Fairfax et al., 2004).

The main regulatory sites on both glutamate receptors and GABABRs are their intracellular C-terminal tails. Depending on the activity or stimulation received by the receptors, the C-terminal domains bind to various proteins including enzymes, scaffolds, and trafficking and signaling proteins (De La Rue and Henley, 2002). These sites sometimes also mediate complex formation during a cross-talk between the receptors. Many immunocytochemical and electron microscopy studies have demonstrated that glutamatergic synapses are enriched with GABABRs (Fritschy et al., 1999; Luján and Shigemoto, 2006). There is also increasing evidence that NMDARs, AMPARs and mGluRs are modulated directly and sometimes indirectly by GABABRs (Morrisett et al., 1991; Hirono et al., 2001; Otmakhova and Lisman, 2004; Tabata et al., 2004; Sun et al., 2006; Chalifoux and Carter, 2010; Gandal et al., 2012; Terunuma et al., 2014). Conversely, GABABR subunits are differentially regulated by glutamate receptor subtypes under various stimulation protocols (Vargas et al., 2008; Cimarosti et al., 2009; Guetg et al., 2010; Maier et al., 2010; Terunuma et al., 2010; Kantamneni et al., 2014). The sections below in this review will follow this theme of regulation or modulation between GABAB and glutamate receptors. This cross-talk provides important regulatory mechanisms, for example, in altering presynaptic release or changes to membrane potential, but also alters the function of glutamate receptors, which may prove useful in a therapeutic context.

GABABR-Mediated Regulation of Glutamate Receptor Function

GABABR Regulation of NMDAR-Dependent Post-Synaptic Calcium Signals

The major synaptic Ca2+ signals in the brain are mediated via NMDARs, which are crucial for activity-dependent changes in synaptic plasticity (Bliss and Collingridge, 1993; Mainen et al., 1999; Malenka and Bear, 2004). These Ca2+ signals are thought to be inhibited by GABAB receptors via modulation of K+ channels, resulting in a hyperpolarization that decreases the Ca2+ influx and overall current by enhancing Mg2+ blockade of NMDARs. (Morrisett et al., 1991; Otmakhova and Lisman, 2004; Deng et al., 2009). Interestingly, it has also been demonstrated recently that Ca2+ influx via NMDARs is inhibited by GABAB receptor activation (Chalifoux and Carter, 2010). This effect on NMDARs is independent of K+ channel and voltage sensitive Ca2+ channel activation, Gβγ subunits and internal Ca2+ stores. Via coupling to Gαi/Gαo G proteins, GABABRs inhibit adenylate cyclase to reduce PKA activity by decreasing cAMP levels. The Ca2+ influx via NMDA receptors is normally increased by PKA activity and reduction of PKA activity by GABABRs inhibits Ca2+ signals (Chalifoux and Carter, 2010). GABABR-mediated postsynaptic modulation through the PKA pathway does not affect synaptic currents mediated by NMDA or AMPA receptors (Chalifoux and Carter, 2010). As outlined below, protein kinases such as PKA and phosphatases such as PP1/2 and calcineurin (CaN) are regulated via AKAPs (A Kinase Anchoring Proteins) and mediate signaling where they act as scaffold molecules (see below for further insights).

NMDAR and GABABR Cross-Talk in Disease

Recently it has been demonstrated that, there is clear interplay between GABAB and NMDA receptors not only in physiological functions but also in pathological situations. Altered NMDAR activity is observed in models of pain and neuropsychiatric disorders, but an interesting phenomenon is that these phenotypes can be rescued with GABABR ligands. For example, in diabetic neuropathy, NMDAR expression is increased in spinal cord dorsal horn, while GABAB receptors are down regulated at protein level (Wang et al., 2011). Using streptozotocin (STZ)-induced diabetic neuropathy rat models (STZ), it has been found that intrathecal injection of the GABABR agonist baclofen significantly increased paw withdrawal threshold. This effect was blocked with pre-treatment of CGP55845, a GABABR—selective antagonist (Bai et al., 2014). In STZ rats, changes in expression were observed in both cyclic AMP response element-binding protein (CREB) and GluN2B, which were significantly increased at the protein (CREB and GluN2B) and mRNA level (GluN2B) in spinal cord. The higher expression levels of both GluN2B and phosphorylated CREB proteins were significantly reduced by administration of baclofen (Liu et al., 2014). Importantly, baclofen-induced reduction of GluN2B and CREB expression was abolished when CGP55845 was pre-administered, suggesting that GABABR activation in the spinal cord dorsal horn can normalize NMDAR expression levels in diabetic neuropathic pain (Wang et al., 2011; Bai et al., 2014; Liu et al., 2014).

In contrast, reduced NMDA receptor functionality has been observed in neuropsychiatric disorders like intellectual disability, autism and schizophrenia (Gonda, 2012). For example, a mouse model expressing a reduced amount of GluN1 subunit (NR1neo−/− mice) was characterized to mimic schizophrenic-like behavior (Mohn et al., 1999). These mice have increased power in the gamma (30–80 Hz) EEG range during rest, but show a reduced auditory-stimulus evoked gamma power (reduced gamma signal-to-noise), causing changes in excitatory/inhibitory balance, and express treatment resistant symptoms of autism and schizophrenia (Gandal et al., 2012). Treating NR1neo−/− mice with baclofen restored excitatory/inhibitory balance, neural synchrony and also improved social function and spatial memory deficits (Gandal et al., 2012). To summarize, diseases characterized by NMDA receptor dysfunction, have the additional possibility of using GABAB receptors as an appropriate target for therapy that could possibly pave the way to restore abnormalities in many other neurological diseases.

GABABR Cross-Talk with AMPARs

Surface expression of AMPA receptors was increased in a knock-in mouse model in which wild-type GABAB2R was replaced with a S783A-mutated version which cannot be phosphorylated (Terunuma et al., 2014). The S783 on GABAB2 subunit is phosphorylated by AMP-dependent protein kinase (AMPK), which in-turn enhances receptor coupling to GIRKs (Kuramoto et al., 2007). Activating NMDARs transiently results in increased phosphorylation whereas prolonged activation results in dephosphorylation of GABABRs by protein phosphatase 2A (PP2A). GABABRs stability at cell surface is due to high constitutive phosphorylation of GABAB2R and dephosphorylation of this subunit selectively targets the receptors for lysosomal degradation (Fairfax et al., 2004; Terunuma et al., 2010). The expression of GABABR was increased with the mutation due to reduced degradation, leading to decreased level of Arc/Arg3.1 protein necessary for memory consolidation. This, in turn, increased the number of excitatory synapses, PSD95 protein expression and cell surface AMPA receptors. This cross-talk demonstrates a crucial role for GABABRs in regulating excitatory synaptic transmission and neuronal architecture (Terunuma et al., 2014).

GABABR Cross-Talk with mGluRs

Long-term depression (LTD) at cerebellar parallel fiber Purkinje cell synapses is a form of synaptic plasticity critical for cerebellar motor learning and requires the activation of the metabotropic glutamate receptor mGluR1 (Ichise et al., 2000; Ito, 2001). GABABRs are concentrated at cerebellar parallel fiber Purkinje cell synapses and have many functions that are both dependent and independent of GABA. GABABRs and mGluR1 are highly co-expressed in cerebellar Purkinje cells, and display very similar subcellular localizations throughout development (Ige et al., 2000; Luján and Shigemoto, 2006; Rives et al., 2009). Electrophysiological studies have shown that at Purkinje cell synapses, GABABR activation inhibits neurotransmitter release by inhibiting calcium channels as well as affecting release processes (Dittman and Regehr, 1996, 1997; Vigot and Batini, 1997). Extracellular Ca2+ interacts with GABABR in cerebellar Purkinje cells, leading to an increase in the glutamate sensitivity of mGluR1. This sensitization of mGluR1 to glutamate is specifically mediated by GABABRs as it is absent in cells from GABAB1−/− animals. It has also been shown that both GPCRs form a complex in cerebellum and that extracellular Ca2+-mediated crosstalk is not mediated via Gi/o proteins (Tabata et al., 2004). Activity-dependent GABABR inhibition by selective antagonists reduces the magnitude of LTD at parallel fiber Purkinje cell synapses (Kamikubo et al., 2007; Rives et al., 2009). In summary GABABRs not only mediate classical synaptic GABAergic neurotransmission but also regulate mGluR signaling and cerebellar synaptic plasticity.

NMDAR-Mediated Regulation of GABABR Function

GABABRs are very stable at cell surface in terms of agonist stimulation and the number of cell surface GABABRs is primarily controlled by glutamate and not GABA in central neurons (Fairfax et al., 2004; Vargas et al., 2008). Sustained application of glutamate leads to GABABR endocytosis, trafficking to lysosomes and subsequent degradation, resulting in a decrease in receptor expression at the cell membrane (Vargas et al., 2008; Maier et al., 2010). Further dissection of the effect of glutamate indicated that activation of AMPA and NMDA receptors is required for the down-regulation of GABABRs and that this effect is enhanced by activation of the group I mGluRs (mGlu1 and mGlu5) (Maier et al., 2010). Activation of NMDARs alone leads to down-regulation and degradation of GABAB1 and GABAB2 subunits, thereby reducing cell surface expression (Guetg et al., 2010; Terunuma et al., 2010; Kantamneni et al., 2014). Mechanistically, NMDAR activation triggers GABAB1 subunit phosphorylation on Ser867 by CaMKII, causing a CaMKII-dependent down regulation (Guetg et al., 2010). In both hippocampal and cortical cultured neurons NMDAR activation also alters the phosphorylation state of GABAB2 subunit on Ser783, resulting in endocytosis and lysosomal degradation of the receptor complex (Terunuma et al., 2010). The GABAB2 subunit is also rapidly phosphorylated by AMPK upon NMDAR activation. Prolonged NMDAR activation subsequently results in GABAB2 subunit dephosphorylation by PP2A, which decreases the number of cell surface receptors (Terunuma et al., 2010).

Recently it has been shown that selective activation of synaptic NMDARs using chemically induced LTP (long-term potentiation) protocol (chem-LTP) leads to an increase in surface GABAB receptors (Kantamneni et al., 2014). In the chem-LTP protocol, glycine (along with strychnine and bicuculline—to block glycine and GABAA receptors, respectively) was used to specifically activate synaptic NMDARs, leading to significant increase in surface expression of AMPARs (Lu et al., 2001; Park et al., 2004). Prolonged activation of extrasynaptic NMDARs promotes cell death, whereas activation of synaptic NMDARs mediates synaptic plasticity and is thought to be involved in neuroprotection via modulation of nuclear Ca2+ signaling (Hardingham and Bading, 2010). Using the chem-LTP method, both GABAB1 and GABAB2 receptor subunit expression on the cell surface were increased in cultured rat hippocampal neurons due to enhanced receptor recycling from intracellular pools (Kantamneni et al., 2014).

GABABR subunits are differentially regulated under oxygen/glucose deprivation (OGD) conditions, which stimulates release of excess glutamate resulting in excitotoxic activation of NMDARs (Papadia and Hardingham, 2007; Cimarosti et al., 2009; Kantamneni et al., 2014). After OGD, expression of GABAB1 subunits at the cell surface is increased via enhanced recycling, while total cellular and cell surface expression levels of GABAB2 subunits are decreased due to reduced recycling (Cimarosti et al., 2009; Kantamneni et al., 2014; Maier et al., 2014). Removing GABAB2 subunit will decrease the number of functional GABABRs, as both subunits are required for normal signaling. In conclusion, the above findings demonstrate that the expression and regulation of GABABR subunits are dynamically regulated in response to synaptic and prolonged/global stimulation of NMDARs. Moreover, NMDAR regulation of GABABRs may be important under conditions of neurological disease, such as epilepsy or ischemia.

Anchoring and Scaffold Proteins as Possible Mediators of GABA/Glutamate Receptor Cross-Talk

Both GABAergic and glutamatergic receptor complexes are regulated and orchestrated by anchoring and scaffold proteins, which are increasingly being implicated in the cross-talk between the two systems. Components of receptor signalosome are typically localized together via scaffold proteins, which co-assemble receptors with regulatory proteins such as protein kinases and phosphatases. AKAPs are typical examples of this class of scaffold proteins (Wong and Scott, 2004). For example, AKAP5 (or AKAP79/150) is thought to localize PKA, protein kinase C (PKC) and the calmodulin-activated protein phosphatase calcineurin (CaN) at specific synaptic sites to regulate excitatory synaptic strength (Gomez et al., 2002; Smith et al., 2006; Robertson et al., 2009; Jurado et al., 2010). AKAP5 is linked to NMDARs via PSD-95 (Colledge et al., 2000). AKAP5 is known to be a master scaffolding protein that links many proteins including kinases, phosphatases, cadherins, F-actin, MAGUKs and PIP2 together with ion channels and receptors to regulate activity dependent signaling processes at synapses (Tunquist et al., 2008; Sanderson and Dell’Acqua, 2011). Many of the proteins binding to AKAP5 (such as PKA, PP2B) also regulate GABABRs and perhaps there is possibility that AKAP5 scaffolding function may be required for glutamate/GABA receptors cross-talk.

Yotiao is another AKAP protein derived from alternative splicing of AKAP9 (also known as AKAP350/450) and plays a major role in regulating NMDARs. Yotiao was first identified as a binding partner of the GluN1 subunit and later found to be an AKAP via its ability to bind PKA-RII subunits in vitro (Lin et al., 1998; Westphal et al., 1999). Yotiao binds both protein phosphatase 1 (PP1) and PKA to form a phosphatase-kinase signaling complex with the GluN1A receptor splice variant. The Yotiao-PP1-PKA complex functions as dual switch, in that activation of anchored PKA enhances NMDAR currents while activation of PP1 exerts an inhibitory effect on NMDAR activity (Westphal et al., 1999; Colledge et al., 2000).

GABAB1Rs were previously shown to interact with a scaffold protein, GISP that enhances cell surface expression of heteromeric complex GABAB1/GABAB2 (Kantamneni et al., 2007). GISP is an AKAP9 C-terminal splice variant with more than 90% similarity to AKAP9 but lacking any RII domain, which are PKA binding sites (Kantamneni et al., 2007). As mentioned previously, the NMDAR binding protein Yotiao is also an AKAP9 splice variant, but within the N-terminal region. Therefore, theoretically, AKAP9 could interact simultaneously with NMDARs and GABABRs as well as regulatory protein kinases and phosphatases. Thus, while speculative, it is tempting to suggest that AKAP9 functions to assemble the signaling complex responsible for mediating the observed cross-talk between the NMDARs and GABABRs. From expression studies it is known that AKAP9 is expressed in the brain and localized to synapses (Collado-Hilly and Coquil, 2009). In similarity to the AKAP5-CaN_PP2B-PKA complex, the AKAP9-PKA-PP1 complex might exist as one large macromolecular complex held together with receptor proteins such as GABABRs and NMDARs. At least in yeast-two hybrid assay it has been confirmed that GISP does not interact with NMDAR sub-type 1 (Kantamneni et al., 2007). GISP binding to other subtypes of NMDARs or Yotiao binding to GABABRs has not been tested, and that this warrants further work. Another protein that may potentially mediate direct crosstalk between GABABR signaling and glutamate receptor signaling is CaMKII. CaMKII is a Ca2+ calmodulin dependent protein kinase, previously been shown to interact with both GABAB and NMDA receptors and regulate NMDAR mediated plasticity (Bayer et al., 2001; Guetg et al., 2010; El Gaamouch et al., 2012). Unlike the earlier examples of indirect receptor modulation, AKAPs and other signaling molecules like CaMKII potentially function as direct links between glutamate and GABAB receptors. If further characterized these complexes may eventually serve as potential drug targets.

Conclusions

Taken together we can conclude that there is very tight regulation between glutamate and GABAB receptors. Regulation of NMDAR-mediated synaptic signals by GABABRs comprises a powerful mechanism for controlling the major excitatory systems in brain. Conversely, NMDAR-mediated control of GABABRs is clearly an important emerging concept in dictating the balance of excitability in the brain. Studying the trafficking and signaling pathways utilized by these excitatory and inhibitory receptors in an integrated manner will undoubtedly provide more understanding of these critical regulatory mechanisms and will ultimately shed light on how the balance between excitatory and inhibitory neurotransmission is dictated in the brain. While many examples of interactions between glutamate and GABAB receptors have been discovered, importantly, the molecular players involved in mediating this cross-talk are only just beginning to be discovered. With this in mind, investigation of the potential players in these processes, such as the AKAPs, is an exciting future avenue of study. Ultimately, targeting these specific regulatory pathways may form the basis of new therapies to treat a number of neurological disorders that are characterized by aberrant balance between excitatory and inhibitory neurotransmitter systems in the brain.

Conflict of Interest Statement

The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Acknowledgments

I thank Dr. Kevin Wilkinson, Dr. Daniel Rocca, Prof. Tim Palmer and Dr. Sonia Correa, for critical comments on manuscript.

References

Bai, H., Liu, P., Wu, Y., Guo, W., Guo, Y., and Wang, X. (2014). Activation of spinal GABAB receptors normalizes N-methyl-D-aspartate receptor in diabetic neuropathy. J. Neurol. Sci. 341, 68–72. doi: 10.1016/j.jns.2014.04.002

PubMed Abstract | Full Text | CrossRef Full Text | Google Scholar

Bayer, K., De Koninck, P., Leonard, A., Hell, J., and Schulman, H. (2001). Interaction with the NMDA receptor locks CaMKII in an active conformation. Nature 411, 801–805. doi: 10.1038/35081080

PubMed Abstract | Full Text | CrossRef Full Text | Google Scholar

Bettler, B., and Tiao, J. (2006). Molecular diversity, trafficking and subcellular localization of GABAB receptors. Pharmacol. Ther. 110, 533–543. doi: 10.1016/j.pharmthera.2006.03.006

PubMed Abstract | Full Text | CrossRef Full Text | Google Scholar

Bliss, T., and Collingridge, G. (1993). A synaptic model of memory: long-term potentiation in the hippocampus. Nature 36, 31–39. doi: 10.1038/361031a0

PubMed Abstract | Full Text | CrossRef Full Text | Google Scholar

Bowery, N., Bettler, B., Froestl, W., Gallagher, J., Marshall, F., Raiteri, M., et al. (2002). International union of pharmacology. XXXIII. Mammalian γ-aminobutyric acid(B) receptors: structure and function. Pharmacol. Rev. 54, 247–264. doi: 10.1124/pr.54.2.247

PubMed Abstract | Full Text | CrossRef Full Text | Google Scholar

Chalifoux, J., and Carter, A. (2010). GABAB receptors modulate NMDA receptor calcium signals in dendritic spines. Neuron 66, 101–113. doi: 10.1016/j.neuron.2010.03.012

PubMed Abstract | Full Text | CrossRef Full Text | Google Scholar

Cherubini, E., Gaiarsa, J., and Ben-Ari, Y. (1991). GABA: an excitatory transmitter in early postnatal life. Trends Neurosci. 14, 515–519. doi: 10.1016/0166-2236(91)90003-d

PubMed Abstract | Full Text | CrossRef Full Text | Google Scholar

Cimarosti, H., Kantamneni, S., and Henley, J. (2009). Ischaemia differentially regulates GABA(B) receptor subunits in organotypic hippocampal slice cultures. Neuropharmacology 56, 1088–1096. doi: 10.1016/j.neuropharm.2009.03.007

PubMed Abstract | Full Text | CrossRef Full Text | Google Scholar

Collado-Hilly, M., and Coquil, J. (2009). Ins(1,4,5)P3 receptor type 1 associates with AKAP9 (AKAP450 variant) and protein kinase A type IIbeta in the Golgi apparatus in cerebellar granule cells. Biol. Cell 101, 469–480. doi: 10.1042/BC20080184

PubMed Abstract | Full Text | CrossRef Full Text | Google Scholar

Colledge, M., Dean, R., Scott, G., Langeberg, L., Huganir, R., and Scott, J. (2000). Targeting of PKA to glutamate receptors through a MAGUK-AKAP complex. Neuron 27, 107–119. doi: 10.1016/s0896-6273(00)00013-1

PubMed Abstract | Full Text | CrossRef Full Text | Google Scholar

Couve, A., Calver, A., Fairfax, B., Moss, S., and Pangalos, M. (2004). Unravelling the unusual signalling properties of the GABA(B) receptor. Biochem. Pharmacol. 68, 1527–1536. doi: 10.1016/j.bcp.2004.06.036

PubMed Abstract | Full Text | CrossRef Full Text | Google Scholar

De La Rue, S. A., and Henley, J. M. (2002). Proteins involved in the trafficking and functional synaptic expression of AMPA and KA receptors. ScientificWorldJournal 2, 461–482. doi: 10.1100/tsw.2002.97

PubMed Abstract | Full Text | CrossRef Full Text | Google Scholar

Deng, P.-Y., Xiao, Z., Yang, C., Rojanathammanee, L., Grisanti, L., Watt, J., et al. (2009). GABA(B) receptor activation inhibits neuronal excitability and spatial learning in the entorhinal cortex by activating TREK-2 K+ channels. Neuron 63, 230–243. doi: 10.1016/j.neuron.2009.06.022

PubMed Abstract | Full Text | CrossRef Full Text | Google Scholar

Dingledine, R., Borges, K., Bowie, D., and Traynelis, S. (1999). The glutamate receptor ion channels. Pharmacol. Rev. 51, 7–61.

PubMed Abstract | Full Text | Google Scholar

Dittman, J. S., and Regehr, W. G. (1996). Contributions of calcium-dependent and calcium-independent mechanisms to presynaptic inhibition at a cerebellar synapse. J. Neurosci. 16, 1623–1633.

PubMed Abstract | Full Text | Google Scholar

Dittman, J., and Regehr, W. (1997). Mechanism and kinetics of heterosynaptic depression at a cerebellar synapse. J. Neurosci. 17, 9048–9059.

PubMed Abstract | Full Text | Google Scholar

El Gaamouch, F., Buisson, A., Moustié, O., Lemieux, M., Labrecque, S., Bontempi, B., et al. (2012). Interaction between αCaMKII and GluN2B controls ERK-dependent plasticity. J. Neurosci. 32, 10767–10779. doi: 10.1523/JNEUROSCI.5622-11.2012

PubMed Abstract | Full Text | CrossRef Full Text | Google Scholar

Fairfax, B., Pitcher, J., Scott, M., Calver, A., Pangalos, M., Moss, S., et al. (2004). Phosphorylation and chronic agonist treatment atypically modulate GABAB receptor cell surface stability. J. Biol. Chem. 279, 12565–12573. doi: 10.1074/jbc.m311389200

PubMed Abstract | Full Text | CrossRef Full Text | Google Scholar

Fritschy, J., Meskenaite, V., Weinmann, O., Honer, M., Benke, D., and Mohler, H. (1999). GABAB-receptor splice variants GB1a and GB1b in rat brain: developmental, regulation, cellular distribution and extrasynaptic localization. Eur. J. Neurosci. 11, 761–768. doi: 10.1046/j.1460-9568.1999.00481.x

PubMed Abstract | Full Text | CrossRef Full Text | Google Scholar

Gainetdinov, R., Premont, R., Bohn, L., Lefkowitz, R., and Caron, M. (2004). Desensitization of G protein-coupled receptors and neuronal functions. Annu. Rev. Neurosci. 27, 107–144. doi: 10.1146/annurev.neuro.27.070203.144206

PubMed Abstract | Full Text | CrossRef Full Text | Google Scholar

Gandal, M., Sisti, J., Klook, K., Ortinski, P., Leitman, V., Liang, Y., et al. (2012). GABAB-mediated rescue of altered excitatory-inhibitory balance, gamma synchrony and behavioral deficits following constitutive NMDAR-hypofunction. Transl. Psychiatry 2:e142. doi: 10.1038/tp.2012.69

PubMed Abstract | Full Text | CrossRef Full Text | Google Scholar

Gomez, L., Alam, S., Smith, K., Horne, E., and Dell’Acqua, M. (2002). Regulation of A-kinase anchoring protein 79/150-cAMP-dependent protein kinase postsynaptic targeting by NMDA receptor activation of calcineurin and remodeling of dendritic actin. J. Neurosci. 22, 7027–7044.

PubMed Abstract | Full Text | Google Scholar

Gonda, X. (2012). Basic pharmacology of NMDA receptors. Curr. Pharm. Des. 18, 1558–1567. doi: 10.2174/138161212799958521

PubMed Abstract | Full Text | CrossRef Full Text | Google Scholar

Guetg, N., Abdel Aziz, S., Holbro, N., Turecek, R., Rose, T., Seddik, R., et al. (2010). NMDA receptor-dependent GABAB receptor internalization via CaMKII phosphorylation of serine 867 in GABAB1. Proc. Natl. Acad. Sci. U S A 107, 13924–13929. doi: 10.1073/pnas.1000909107

PubMed Abstract | Full Text | CrossRef Full Text | Google Scholar

Hardingham, G. E., and Bading, H. (2010). Synaptic versus extrasynaptic NMDA receptor signalling: implications for neurodegenerative disorders. Nat. Rev. Neurosci. 11, 682–696. doi: 10.1038/nrn2911

PubMed Abstract | Full Text | CrossRef Full Text | Google Scholar

Hirono, M., Yoshioka, T., and Konishi, S. (2001). GABA(B) receptor activation enhances mGluR-mediated responses at cerebellar excitatory synapses. Nat. Neurosci. 4, 1207–1216. doi: 10.1038/nn764

PubMed Abstract | Full Text | CrossRef Full Text | Google Scholar

Hollmann, M., and Heinemann, S. (1994). Cloned glutamate receptors. Annu. Rev. Neurosci. 17, 31–108. doi: 10.1146/annurev.neuro.17.1.31

PubMed Abstract | Full Text | CrossRef Full Text | Google Scholar

Ichise, T., Kano, M., Hashimoto, K., Yanagihara, D., Nakao, K., Shigemoto, R., et al. (2000). mGluR1 in cerebellar Purkinje cells essential for long-term depression, synapse elimination and motor coordination. Science 288, 1832–1835. doi: 10.1126/science.288.5472.1832

PubMed Abstract | Full Text | CrossRef Full Text | Google Scholar

Ige, A., Bolam, J., Billinton, A., White, J., Marshall, F., and Emson, P. (2000). Cellular and sub-cellular localisation of GABA(B1) and GABA(B2) receptor proteins in the rat cerebellum. Brain Res. Mol. Brain Res. 83, 72–80. doi: 10.1016/s0169-328x(00)00199-6

PubMed Abstract | Full Text | CrossRef Full Text | Google Scholar

Ito, M. (2001). Cerebellar long-term depression: characterization, signal transduction and functional roles. Physiol. Rev. 81, 1143–1195.

PubMed Abstract | Full Text | Google Scholar

Jurado, S., Biou, V., and Malenka, R. (2010). A calcineurin/AKAP complex is required for NMDA receptor-dependent long-term depression. Nat. Neurosci. 13, 1053–1055. doi: 10.1038/nn.2613

PubMed Abstract | Full Text | CrossRef Full Text | Google Scholar

Kamikubo, Y., Tabata, T., Kakizawa, S., Kawakami, D., Watanabe, M., Ogura, A., et al. (2007). Postsynaptic GABAB receptor signalling enhances LTD in mouse cerebellar Purkinje cells. J. Physiol. 585, 549–563. doi: 10.1113/jphysiol.2007.141010

PubMed Abstract | Full Text | CrossRef Full Text | Google Scholar

Kantamneni, S., Corrêa, S., Hodgkinson, G., Meyer, G., Vinh, N., Henley, J., et al. (2007). GISP: a novel brain-specific protein that promotes surface expression and function of GABA(B) receptors. J. Neurochem. 100, 1003–1017. doi: 10.1111/j.1471-4159.2006.04271.x

PubMed Abstract | Full Text | CrossRef Full Text | Google Scholar

Kantamneni, S., Gonzàlez-Gonzàlez, I., Luo, J., Cimarosti, H., Jacobs, S., Jaafari, N., et al. (2014). Differential regulation of GABAB receptor trafficking by different modes of N-methyl-D-aspartate (NMDA) receptor signaling. J. Biol. Chem. 289, 6681–6694. doi: 10.1074/jbc.M113.487348

PubMed Abstract | Full Text | CrossRef Full Text | Google Scholar

Kuramoto, N., Wilkins, M., Fairfax, B., Revilla-Sanchez, R., Terunuma, M., Tamaki, K., et al. (2007). Phospho-dependent functional modulation of GABA(B) receptors by the metabolic sensor AMP-dependent protein kinase. Neuron 53, 233–247. doi: 10.1016/j.neuron.2006.12.015

PubMed Abstract | Full Text | CrossRef Full Text | Google Scholar

Lin, J., Wyszynski, M., Madhavan, R., Sealock, R., Kim, J., and Sheng, M. (1998). Yotiao, a novel protein of neuromuscular junction and brain that interacts with specific splice variants of NMDA receptor subunit NR1. J. Neurosci. 18, 2017–2027.

PubMed Abstract | Full Text | Google Scholar

Liu, P., Guo, W., Zhao, X., Bai, H., Wang, Q., Wang, X., et al. (2014). Intrathecal baclofen, a GABAB receptor agonist, inhibits the expression of p-CREB and NR2B in the spinal dorsal horn in rats with diabetic neuropathic pain. Can. J. Physiol. Pharmacol. 92, 655–660. doi: 10.1139/cjpp-2013-0463

PubMed Abstract | Full Text | CrossRef Full Text | Google Scholar

Lodge, D. (2009). The history of the pharmacology and cloning of ionotropic glutamate receptors and the development of idiosyncratic nomenclature. Neuropharmacology 56, 6–21. doi: 10.1016/j.neuropharm.2008.08.006

PubMed Abstract | Full Text | CrossRef Full Text | Google Scholar

Lu, W., Man, H., Ju, W., Trimble, W., MacDonald, J. F., and Wang, Y. T. (2001). Activation of synaptic NMDA receptors induces membrane insertion of new AMPA receptors and LTP in cultured hippocampal neurons. Neuron 29, 243–254. doi: 10.1016/s0896-6273(01)00194-5

PubMed Abstract | Full Text | CrossRef Full Text | Google Scholar

Luján, R., and Shigemoto, R. (2006). Localization of metabotropic GABA receptor subunits GABAB1 and GABAB2 relative to synaptic sites in the rat developing cerebellum. Eur. J. Neurosci. 23, 1479–1490. doi: 10.1111/j.1460-9568.2006.04669.x

PubMed Abstract | Full Text | CrossRef Full Text | Google Scholar

Maier, P., Marin, I., Grampp, T., Sommer, A., and Benke, D. (2010). Sustained glutamate receptor activation down-regulates GABAB receptors by shifting the balance from recycling to lysosomal degradation. J. Biol. Chem. 285, 35606–35614. doi: 10.1074/jbc.M110.142406

PubMed Abstract | Full Text | CrossRef Full Text | Google Scholar

Maier, P., Zemoura, K., Acuña, M., Yévenes, G., Zeilhofer, H., and Benke, D. (2014). Ischemia-like oxygen and glucose deprivation mediates down-regulation of cell surface γ-aminobutyric acidB receptors via the endoplasmic reticulum (ER) stress-induced transcription factor CCAAT/enhancer-binding protein (C/EBP)-homologous protein (CHOP). J. Biol. Chem. 289, 12896–12907. doi: 10.1074/jbc.M114.550517

PubMed Abstract | Full Text | CrossRef Full Text | Google Scholar

Mainen, Z., Malinow, R., and Svoboda, K. (1999). Synaptic calcium transients in single spines indicate that NMDA receptors are not saturated. Nature 399, 151–155. doi: 10.1038/20187

PubMed Abstract | Full Text | CrossRef Full Text | Google Scholar

Malenka, R. C., and Bear, M. F. (2004). LTP and LTD: an embarrassment of riches. Neuron 44, 5–21. doi: 10.1016/j.neuron.2004.09.012

PubMed Abstract | Full Text | CrossRef Full Text | Google Scholar

Malitschek, B., Schweizer, C., Keir, M., Heid, J., Froestl, W., Mosbacher, J., et al. (1999). The N-terminal domain of γ-aminobutyric Acid(B) receptors is sufficient to specify agonist and antagonist binding. Mol. Pharmacol. 56, 448–454.

PubMed Abstract | Full Text | Google Scholar

Marshall, F. H., Jones, K. A., Kaupmann, K., and Bettler, B. (1999). GABAB receptors—the first 7TM heterodimers. Trends Pharmacol. Sci. 20, 396–399. doi: 10.1016/s0165-6147(99)01383-8

PubMed Abstract | Full Text | CrossRef Full Text

Mattson, M. (2008). Glutamate and neurotrophic factors in neuronal plasticity and disease. Ann. N Y Acad. Sci. 1144, 97–112. doi: 10.1196/annals.1418.005

PubMed Abstract | Full Text | CrossRef Full Text | Google Scholar

Mohn, A., Gainetdinov, R., Caron, M., and Koller, B. (1999). Mice with reduced NMDA receptor expression display behaviours related to schizophrenia. Cell 98, 427–436. doi: 10.1016/s0092-8674(00)81972-8

PubMed Abstract | Full Text | CrossRef Full Text | Google Scholar

Morrisett, R., Mott, D., Lewis, D., Swartzwelder, H., and Wilson, W. (1991). GABAB-receptor-mediated inhibition of the N-methyl-D-aspartate component of synaptic transmission in the rat hippocampus. J. Neurosci. 11, 203–209.

PubMed Abstract | Full Text | Google Scholar

Musazzi, L., Treccani, G., Mallei, A., and Popoli, M. (2013). The action of antidepressants on the glutamate system: regulation of glutamate release and glutamate receptors. Biol. Psychiatry 12, 1180–1188. doi: 10.1016/j.biopsych.2012.11.009

PubMed Abstract | Full Text | CrossRef Full Text | Google Scholar

Nakanishi, S., Nakajima, Y., Masu, M., Ueda, Y., Nakahara, K., Watanabe, D., et al. (1998). Glutamate receptors: brain function and signal transduction. Brain Res. Brain Res. Rev. 26, 230–235. doi: 10.1016/S0165-0173(97)00033-7

PubMed Abstract | Full Text | CrossRef Full Text | Google Scholar

Nicoletti, F., Bockaert, J., Collingridge, G., Conn, P., Ferraguti, F., Schoepp, D., et al. (2011). Metabotropic glutamate receptors: from the workbench to the bedside. Neuropharmacology 60, 1017–1041. doi: 10.1016/j.neuropharm.2010.10.022

PubMed Abstract | Full Text | CrossRef Full Text | Google Scholar

Otmakhova, N., and Lisman, J. (2004). Contribution of Ih and GABAB to synaptically induced afterhyperpolarizations in CA1: a brake on the NMDA response. J. Neurophysiol. 92, 2027–2039. doi: 10.1152/jn.00427.2004

PubMed Abstract | Full Text | CrossRef Full Text | Google Scholar

Papadia, S., and Hardingham, G. E. (2007). The dichotomy of NMDA receptor signaling. Neuroscientist 13, 572–579. doi: 10.1177/1073858407305833

PubMed Abstract | Full Text | CrossRef Full Text | Google Scholar

Park, M., Penick, E., Edwards, J., Kauer, J., and Ehlers, M. (2004). Recycling endosomes supply AMPA receptors for LTP. Science 305, 1972–1975. doi: 10.1126/science.1102026

PubMed Abstract | Full Text | CrossRef Full Text | Google Scholar

Rives, M., Vol, C., Fukazawa, Y., Tinel, N., Trinquet, E., Ayoub, M., et al. (2009). Crosstalk between GABAB and mGlu1a receptors reveals new insight into GPCR signal integration. EMBO J. 28, 2195–2208. doi: 10.1038/emboj.2009.177

PubMed Abstract | Full Text | CrossRef Full Text | Google Scholar

Robbins, M., Calver, A., Filippov, A., Hirst, W., Russell, R., Wood, M., et al. (2001). GABA(B2) is essential for g-protein coupling of the GABA(B) receptor heterodimer. J. Neurosci. 21, 8043–8052.

PubMed Abstract | Full Text | Google Scholar

Robertson, H., Gibson, E., Benke, T., and Dell’Acqua, M. (2009). Regulation of postsynaptic structure and function by an A-kinase anchoring protein-membrane-associated guanylate kinase scaffolding complex. J. Neurosci. 29, 7929–7943. doi: 10.1523/JNEUROSCI.6093-08.2009

PubMed Abstract | Full Text | CrossRef Full Text | Google Scholar

Sanderson, J. L., and Dell’Acqua, M. L. (2011). AKAP signaling complexes in regulation of excitatory synaptic plasticity. Neuroscientist 3, 321–336. doi: 10.1177/1073858410384740

PubMed Abstract | Full Text | CrossRef Full Text | Google Scholar

Sheng, M., and Kim, E. (2011). The postsynaptic organization of synapses. Cold Spring Harb. Perspect. Biol. 3:a005678. doi: 10.1101/cshperspect.a005678

PubMed Abstract | Full Text | CrossRef Full Text | Google Scholar

Smith, K., Gibson, E., and Dell’Acqua, M. (2006). cAMP-dependent protein kinase postsynaptic localization regulated by NMDA receptor activation through translocation of an A-kinase anchoring protein scaffold protein. J. Neurosci. 26, 2391–2402. doi: 10.1523/jneurosci.3092-05.2006

PubMed Abstract | Full Text | CrossRef Full Text | Google Scholar

Sun, H., Ma, C., Kelly, J., and Wu, S. (2006). GABAB receptor-mediated presynaptic inhibition of glutamatergic transmission in the inferior colliculus. Neurosci. Lett. 399, 151–156. doi: 10.1016/j.neulet.2006.01.049

PubMed Abstract | Full Text | CrossRef Full Text | Google Scholar

Tabata, T., Araishi, K., Hashimoto, K., Hashimotodani, Y., van der Putten, H., Bettler, B., et al. (2004). Ca2+ activity at GABAB receptors constitutively promotes metabotropic glutamate signaling in the absence of GABA. Proc. Natl. Acad. Sci. U S A 101, 16952–16957. doi: 10.1073/pnas.0405387101

PubMed Abstract | Full Text | CrossRef Full Text | Google Scholar

Takahashi, T., Kajikawa, Y., and Tsujimoto, T. (1998). G-Protein-coupled modulation of presynaptic calcium currents and transmitter release by a GABAB receptor. J. Neurosci. 18, 3138–3146.

PubMed Abstract | Full Text | Google Scholar

Terunuma, M., Revilla-Sanchez, R., Quadros, I., Deng, Q., Deeb, T., Lumb, M., et al. (2014). Postsynaptic GABAB receptor activity regulates excitatory neuronal architecture and spatial memory. J. Neurosci. 34, 804–816. doi: 10.1523/JNEUROSCI.3320-13.2013

PubMed Abstract | Full Text | CrossRef Full Text | Google Scholar

Terunuma, M., Vargas, K., Wilkins, M., Ramírez, O., Jaureguiberry-Bravo, M., Pangalos, M., et al. (2010). Prolonged activation of NMDA receptors promotes dephosphorylation and alters postendocytic sorting of GABAB receptors. Proc. Natl. Acad. Sci. U S A 107, 13918–13923. doi: 10.1073/pnas.1000853107

PubMed Abstract | Full Text | CrossRef Full Text | Google Scholar

Tunquist, B., Hoshi, N., Guire, E., Zhang, F., Mullendorff, K., Langeberg, L., et al. (2008). Loss of AKAP150 perturbs distinct neuronal processes in mice. Proc. Natl. Acad. Sci. U S A 105, 12557–12562. doi: 10.1073/pnas.0805922105

PubMed Abstract | Full Text | CrossRef Full Text | Google Scholar

Vargas, K., Terunuma, M., Tello, J., Pangalos, M., Moss, S., and Couve, A. (2008). The availability of surface GABA B receptors is independent of gamma-aminobutyric acid but controlled by glutamate in central neurons. J. Biol. Chem. 283, 24641–24648. doi: 10.1074/jbc.M802419200

PubMed Abstract | Full Text | CrossRef Full Text | Google Scholar

Vigot, R., and Batini, C. (1997). GABA(B) receptor activation of Purkinje cells in cerebellar slices. Neurosci. Res. 29, 151–160. doi: 10.1016/s0168-0102(97)00087-4

PubMed Abstract | Full Text | CrossRef Full Text | Google Scholar

Wang, X., Zhang, Q., Zhang, Y., Liu, Y., Dong, R., Wang, Q., et al. (2011). Downregulation of GABAB receptors in the spinal cord dorsal horn in diabetic neuropathy. Neurosci. Lett. 490, 112–115. doi: 10.1016/j.neulet.2010.12.038

PubMed Abstract | Full Text | CrossRef Full Text | Google Scholar

Watanabe, M., Maemura, K., Kanbara, K., Tamayama, T., and Hayasaki, H. (2002). GABA and GABA receptors in the central nervous system and other organs. Int. Rev. Cytol. 213, 1–47. doi: 10.1016/s0074-7696(02)13011-7

PubMed Abstract | Full Text | CrossRef Full Text | Google Scholar

Westphal, R., Tavalin, S., Lin, J., Alto, N., Fraser, I., and Langeberg, L. (1999). Regulation of NMDA receptors by an associated phosphatase-kinase signaling complex. Science 285, 93–96. doi: 10.1126/science.285.5424.93

PubMed Abstract | Full Text | CrossRef Full Text | Google Scholar

Wong, W., and Scott, J. (2004). AKAP signalling complexes: focal points in space and time. Nat. Rev. Mol. Cell Biol. 5, 959–970. doi: 10.1038/nrm1527

PubMed Abstract | Full Text | CrossRef Full Text | Google Scholar

Wu, L. G., and Saggau, P. (1995). GABAB receptor-mediated presynaptic inhibition in guinea-pig hippocampus is caused by reduction of presynaptic Ca2+ influx. J. Physiol. 485, 649–657. doi: 10.1113/jphysiol.1995.sp020759

PubMed Abstract | Full Text | CrossRef Full Text | Google Scholar

Keywords: glutamate receptor, NMDAR, GABABR, AMPAR, AKAP, receptor regulation, receptor trafficking and mGluR

Citation: Kantamneni S (2015) Cross-talk and regulation between glutamate and GABAB receptors. Front. Cell. Neurosci. 9:135. doi: 10.3389/fncel.2015.00135

Received: 17 October 2014; Accepted: 23 March 2015;
Published online: 10 April 2015.

Edited by:

Milos Petrovic, University of Belgrade, Serbia

Reviewed by:

Rostislav Turecek, Academy of Sciences of Czech Republic, Czech Republic
William Martin Connelly, Cardiff University, UK

Copyright © 2015 Kantamneni. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution and reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

*Correspondence: Sriharsha Kantamneni, Bradford School of Pharmacy, School of Life Sciences, University of Bradford, Norcroft Building 2.12, Richmond Road, Bradford, West Yorkshire - BD7 1DP, UK Tel: 0044 (0) 1274 236072 s.kantamneni@bradford.ac.uk