1521-0111/89/2/273–286$25.00 http://dx.doi.org/10.1124/mol.115.102210 MOLECULAR PHARMACOLOGY Mol Pharmacol 89:273–286, February 2016 Copyright ª 2016 by The American Society for Pharmacology and Experimental Therapeutics MINIREVIEW Roles for Regulator of G Protein Signaling Proteins in Synaptic Signaling and Plasticity Kyle J. Gerber, Katherine E. Squires, and John R. Hepler Programs in Molecular and Systems Pharmacology (K.J.G., K.E.S., J.R.H.) and Neuroscience (J.R.H.), Department of Downloaded from Pharmacology (K.J.G., K.E.S., J.R.H.), Emory University School of Medicine, Atlanta, Georgia Received October 26, 2015; accepted December 10, 2015 ABSTRACT The regulator of G protein signaling (RGS) family of proteins synaptic transmission, and synaptic plasticity, which are neces- molpharm.aspetjournals.org serves critical roles in G protein-coupled receptor (GPCR) and sary for central nervous system physiology and behavior. heterotrimeric G protein signal transduction. RGS proteins are Accumulating evidence has revealed key roles for specific RGS best understood as negative regulators of GPCR/G protein proteins in multiple signaling pathways at neuronal synapses, signaling. They achieve this by acting as GTPase activating regulating both pre- and postsynaptic signaling events and proteins (GAPs) for Ga subunits and accelerating the turnoff of G synaptic plasticity. Here, we review and highlight the current protein signaling. Many RGS proteins also bind additional knowledge of specific RGS proteins (RGS2, RGS4, RGS7, signaling partners that either regulate their functions or enable RGS9-2, and RGS14) that have been clearly demonstrated to them to regulate other important signaling events. At neuronal serve critical roles in modulating synaptic signaling and plasticity synapses, GPCRs, G proteins, and RGS proteins work in throughout the brain, and we consider their potential as future coordination to regulate key aspects of neurotransmitter release, therapeutic targets. at ASPET Journals on September 27, 2021 Introduction termination of downstream signaling by both the Ga and Gbg subunits (De Vries et al., 2000; Ross and Wilkie, 2000; G protein coupled receptors (GPCRs) are necessary for Hollinger and Hepler, 2002; Willars, 2006). RGS proteins functional neurotransmission throughout the central nervous are a structurally diverse family of signaling proteins with system, controlling neurophysiological processes ranging from many identified signaling partners distinct from Ga and movement to mood (Lagerström and Schiöth, 2008; Betke GPCRs. In this regard, considerable evidence shows that et al., 2012; Rojas and Dingledine, 2013). Receptor activation many RGS proteins have cell signaling roles in addition to of heterotrimeric G proteins (Gabg) results in release of Ga- their shared established roles as GAPs for Ga subunits GTP and Gbg that stimulate downstream effectors and second (Burchett, 2000; Abramow-Newerly et al., 2006; Sethakorn messenger pathways to mediate intracellular physiology et al., 2010). (Bourne et al., 1990; Simon et al., 1991; Hepler and Gilman, GPCR signaling regulates key aspects of both pre- and 1992; Hamm, 1998). GPCR and linked G protein signaling is postsynaptic neurotransmission, leading to changes in synap- tightly controlled by the family of regulator of G protein tic plasticity, including long-term potentiation (LTP), long- signaling (RGS) proteins. RGS proteins act as GTPase acti- term depression (LTD), reversal of LTP (depotentiation), and vating proteins (GAPs) on the a subunits of the Ga and Ga i q presynaptic vesicle release potential. Various metabotropic subfamilies of heterotrimeric G proteins, greatly enhancing GPCRs either positively or negatively regulate presynaptic the intrinsic GTPase activity of the Ga subunit to facilitate the neurotransmitter release (Tedford and Zamponi, 2006; Betke et al., 2012). On postsynaptic membranes, GPCRs and G Work in the Hepler Laboratory on this topic is supported by the National protein signaling pathways regulate neuronal excitability, Institutes of Health grants [Grants R01NS37112 and 1R21NS087488] to J.R.H.; modulating fast-acting neurotransmission mediated by additionally, both K.J.G. and K.E.S. were supported by National Institutes of Health training grants [Grant T32 GM008602]. ligand-gated ion channels, including glutamate (Liu et al., dx.doi.org/10.1124/mol.115.102210. 2006; Chalifoux and Carter, 2010; Rojas and Dingledine, 2013) ABBREVIATIONS: CaV, voltage-gated calcium; DEP, disheveled, Egl-10, and pleckstrin; D2DR, D2 dopamine receptor; eCB, endocannabinoid; ERK, extracellular signal-regulated kinase; GABA, g-aminobutyric acid; GABABR, g-aminobutyric acid B receptor; GAP, GTPase activating protein; GIRK, G protein-coupled inwardly rectifying potassium; GPR, G protein regulatory; GPCR, G protein-coupled receptor; Gb5, G protein b5; KO, knockout; LTD, long-term depression; LTP, long-term potentiation; MOR, m-opioid receptor; NMDA, N-methyl-D-aspartate; PD, Parkinson’s disease; PPF, paired pulse facilitation; RGS, regulator of G protein signaling; R7BP, R7-binding protein; VTA, ventral tegmental area. 273 274 Gerber et al. and g-aminobutyric acid (GABA) receptors (Bormann, 1988). and nucleus accumbens) of rats following amphetamine ad- Following GPCR activation of Ga, released Gbg directly binds ministration (Taymans et al., 2002). In a model more closely to and activates G protein-coupled inwardly rectifying potas- related to synaptic plasticity, high-frequency stimulation, sium (GIRK) channels. GIRK channels hyperpolarize the which is commonly used to induce hippocampal LTP, has neuron and dampen the overall capacity of the postsynaptic been shown to strongly induce the expression of RGS2 mRNA signaling to potentiate (Dascal, 1997), a process known as within the dentate gyrus of the hippocampus (Ingi et al., depotentiation, or the reversal of LTP. As such, GIRK chan- 1998). Furthermore, stable expression of RGS2 with no nels are required for depotentiation and many RGS proteins induction protocol has been found throughout the brain in regulate the rate at which GPCR-coupled GIRK channels close the same regions in which its expression is induced: the hip- following agonist removal (Doupnik et al., 1997; Saitoh et al., pocampus, cortex, striatum, ventral tegmental area (VTA), 1997, 2001; Ulens et al., 2000). Presynaptically, active Gbg and amygdala (Grafstein-Dunn et al., 2001; Ingi and Aoki, subunits can inhibit voltage-gated calcium (CaV) channels 2002; Taymans et al., 2002). necessary for calcium-dependent neurotransmitter release Due to its high expression throughout the brain and its following an action potential (Bormann, 1988; Zamponi and unique role as an immediate early gene, functions for RGS2 Currie, 2013). In this case, RGS proteins can antagonize the in neurologic diseases and disorders have been extensively effects of Gbg on N- and P/Q-type CaV channels (CaV2.2 and studied. Multiple reports have shown a role for this RGS Downloaded from CaV2.1), facilitating neurotransmitter release (Kammermeier protein in modulating anxiety, with polymorphisms in RGS2 and Ikeda, 1999; Jeong and Ikeda, 2000; Mark et al., 2000). associated with generalized anxiety disorder (Smoller et al., Additionally, canonical heterotrimeric G protein signaling 2008; Koenen et al., 2009; Hohoff et al., 2015), panic disorder through Ga subunits has been shown to affect plasticity via (Koenen et al., 2009; Otowa et al., 2011; Hohoff et al., 2015), modulation of postsynaptic glutamate receptors (Liu et al., post-traumatic stress disorder (Amstadter et al., 2009), as 2006; Chalifoux and Carter, 2010) and multiple other signal- well as suicide (Cui et al., 2008) in humans. Studies in mice ing pathways necessary for synaptic plasticity. have also shown an association between RGS2 and anxiety molpharm.aspetjournals.org Our current understanding of roles for RGS proteins in (Oliveira-Dos-Santos et al., 2000; Yalcin et al., 2004; Lifschytz physiology and behavior has been greatly aided by the devel- et al., 2012; Okimoto et al., 2012) with decreased RGS2 opment and use of RGS-insensitive Ga subunits (DiBello expression causing anxiety (Oliveira-Dos-Santos et al., 2000; et al., 1998; Fu et al., 2004; Kaur et al., 2011), allowing Lifschytz et al., 2012) and depression-like (Lifschytz et al., examination of neurophysiology under conditions that mimic 2012) phenotypes. To better treat these diseases associated functional uncoupling of Ga-RGS. Studies with these mutants with RGS2, it is necessary to understand how RGS2 modu- have revealed key roles for RGS proteins in multiple signaling lates synaptic plasticity and signaling. pathways in neurons, as well as pre- and postsynaptic signal- Functions for RGS2 in synaptic signaling and plasticity ing and plasticity specifically (Chen and Lambert, 2000; have been examined largely within the hippocampus and at ASPET Journals on September 27, 2021 Goldenstein et al., 2009; Talbot et al., 2010). By examining VTA. Within the hippocampus, RGS2 regulates short-term the role of RGS proteins in synaptic signaling, we can better synaptic plasticity. High concentrations of RGS2 within the understand the function of GPCR and G protein signaling in neuron appear to facilitate paired pulse depression, while low synaptic plasticity as well as diseases associated with RGS expression of RGS2 leads to paired pulse facilitation (PPF). In protein dysfunction. Here, we highlight and review our other words, probability of neurotransmitter release