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Regulation of Neuronal Communication by G Protein-Coupled Receptors ⇑ Yunhong Huang, Amantha Thathiah

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Regulation of Neuronal Communication by G Protein-Coupled Receptors ⇑ Yunhong Huang, Amantha Thathiah View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Elsevier - Publisher Connector FEBS Letters 589 (2015) 1607–1619 journal homepage: www.FEBSLetters.org Review Regulation of neuronal communication by G protein-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 neurons. 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 exocytosis machinery, neurotransmitter 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 neurotransmission, 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 Autoreceptors Neurotransmitters 1. Introduction serotonin; (3) the neuropeptides; 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 axon 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 secretion of chemical messengers restricted to certain neuronal structures, and can diffuse over very called neurotransmitters at chemical synapses 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), glycine, acetylcholine, 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 dopamine, noradrenaline, adrenaline, histamine, 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 nerve terminals, such Recent breakthrough developments in protein engineering and as sympathetic axons, 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 receptor 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 hormone 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. Ligand 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, hormones, 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 synapse 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 autoreceptor 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
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