Downloaded from http://cshperspectives.cshlp.org/ on October 2, 2021 - Published by Cold Spring Harbor Laboratory Press Synaptic Neurotransmitter-Gated Receptors Trevor G. Smart1 and Pierre Paoletti2 1Department of Neuroscience, Physiology & Pharmacology, University College London, London WC1E 6BT, United Kingdom 2Institut de Biologie de l’Ecole Normale Supe´rieure (IBENS), CNRS UMR8197, INSERM U1024, Ecole Normale Supe´rieure, 75005 Paris, France Correspondence: [email protected]; [email protected] Since the discovery of the major excitatory and inhibitory neurotransmitters and their receptors in the brain, many have deliberated over their likely structures and how these may relate to function. This was initially satisfied by the determination of the first amino acid sequences of the Cys-loop receptors that recognized acetylcholine, serotonin, GABA, and glycine, followed later by similar determinations for the glutamate receptors, comprising non-NMDA and NMDA subtypes. The last decade has seen a rapid advance resulting in the first structures of Cys-loop receptors, related bacterial and molluscan homologs, and gluta- mate receptors, determined down to atomic resolution. This now provides a basis for deter- mining not just the complete structures of these important receptor classes, but also for understanding how various domains and residues interact during agonist binding, receptor activation, and channel opening, including allosteric modulation. This article reviews our current understanding of these mechanisms for the Cys-loop and glutamate receptor families. o understand how neurons communicate neuronal excitation and inhibition. For excita- Twith each other requires a fundamental un- tion, the principal neurotransmitter involved is derstanding of neurotransmitter receptor struc- glutamate, which interacts with ionotropic (inte- ture and function. Neurotransmitter-gated ion gral ion channel) and metabotropic (second- channels, also known as ionotropic receptors, messenger signaling) receptors. The ionotropic are responsible for fast synaptic transmission. glutamate receptors are permeable to cations, They decode chemical signals into electrical re- which directly cause excitation. Acetylcholine sponses, thereby transmitting information from and serotonin can also activate specific cation- one neuron to another. Their suitability for this selective ionotropic receptors to affect neuronal important task relies on their ability to respond excitation. For controlling cell excitability, inhib- very rapidly to the transient release of neuro- ition is important, and this is mediated by the transmitter to affect cell excitability. neurotransmitters GABA and glycine, causing In the central nervous system (CNS), fast syn- an increased flux of anions. GABA predominates aptic transmission results in two main effects: as the major inhibitory transmitter throughout Editors: Morgan Sheng, Bernardo Sabatini, and Thomas Su¨dhof Additional Perspectives on The Synapse available at www.cshperspectives.org Copyright # 2012 Cold Spring Harbor Laboratory Press; all rights reserved; doi: 10.1101/cshperspect.a009662 Cite this article as Cold Spring Harb Perspect Biol 2012;4:a009662 1 Downloaded from http://cshperspectives.cshlp.org/ on October 2, 2021 - Published by Cold Spring Harbor Laboratory Press T.G. Smart and P. Paoletti the CNS, whereas glycine is of greater importance loop receptors, although much remains to be in the spinal cord and brainstem. They both acti- discovered. vate specific receptors—for GABA, there are ion- otropic and metabotropic receptors, whereas for Cys-Loop Receptor Gene Families glycine, only ionotropic receptors are known to date. The founding members were defined as “Cys- Togetherwith acetylcholine- and serotonin- loop receptors” because they contain a highly gated channels, GABA and glycine ionotropic conserved structural signature—a loop formed receptors form the superfamily of Cys-loop re- by a disulfide bridge in the extracellular do- ceptors, which differs in many aspects from the main. They are nicotinic acetylcholine receptors superfamily of ionotropic glutamate receptors. (nAChR), type 3 5-hydroxytryptamine receptors Over the last two decades, our knowledge of (5HT3R), g-aminobutyric acid receptors (type the structure and function of ionotropic recep- A and C, GABAA/CR), and glycine receptors tors has grown rapidly. In this article, we sum- (GlyR) (Barnard et al. 1987; Grenningloh et al. marize our current understanding of the molec- 1987; Betz 1990). Also included are the Zn2þ- ular operation of these receptors and how we activated cation channel (Davies et al. 2003) can now begin to interpret the role of receptor and invertebrate receptors activated either by structure in agonist binding, channel activation, glutamate or serotonin (anionic channels) or and allosteric modulation of Cys-loop and glu- GABA (cationic channels) (Ortells and Lunt tamate receptor families. Further details on the 1995; Lester et al. 2004), but the related bacterial regulation and trafficking of neurotransmitter homologs, Gloeobacter violaceus (GLIC) (Boc- receptors in synaptic structure and plasticity can quet et al. 2009) and Erwinia chrysanthemi be found in accompanying articles. (ELIC) (Hilf and Dutzler 2008), lack the char- acteristic Cys-loop signature. Consequently, Cys-loop receptors are more precisely referred CYS-LOOP RECEPTOR SUPERFAMILY to as “pentameric ligand-gated ion channels.” In the central and peripheral nervous systems, Their diversity is extensive, with most sub- neurotransmitter-gated ion channels underpin unit families encoded by multiple genes. For the rapid transfer of information between neu- the major ligand-gated anion channels, such rons by permitting the passage of ions across the as GABAA/CRs, eight subunit families have cell membrane. They are located at presynaptic been identified (a1-6, b1-3, g1-3, d, 1, p, u, and postsynaptic sites to affect the excitability and r1-3), yielding 19 subunits. Although mul- of neurons and muscle. Within a few millisec- tiple subunit combinations are possible, promi- onds following a presynaptic action potential, nent among these are abg (stoichiometry 2:2:1) receptors bind neurotransmitter molecules to and abd. In contrast, the r-subunits preferen- initiate channel opening. These channels close tially combine together forming either homo- just as rapidly after the dissociation of neuro- meric or heteromeric receptors that are referred transmitters to terminate synaptic events. The to as GABACRs; for GlyRs, two subunit families importance of these receptors is exemplified exist, a1-4 and b, yielding a total of five sub- by the diseases that are caused following their units. Early on during development, GlyRs dysfunction and by the increasing number of form a-subunit homomers, later changing to therapeutic agents that target them. Postsynap- ab heteromers (Alexander et al. 2008). tic receptors are not confined to synapses— The major ligand-gated cation channels in- their extrasynaptic counterparts are responsive clude the extensive nAChR family. Five subunit to low levels of neurotransmitter mediating a families are known (a1-7, 9 and 10, b1-4, d, 1, persistent tonic control over cell activity. Thus, and g), providing 16 subunits in vertebrates. their roles are manifold, and with improved Subunit combinations at the neuromuscular structural techniques, it is now possible to as- junction are well known (embryonic: a2bgd; sign some function to various domains of Cys- and adult: a2b1d). For neuronal nAChRs, sub- 2 Cite this article as Cold Spring Harb Perspect Biol 2012;4:a009662 Downloaded from http://cshperspectives.cshlp.org/ on October 2, 2021 - Published by Cold Spring Harbor Laboratory Press Synaptic Neurotransmitter-Gated Receptors unit assemblies are less clear with ab combina- ishing receptors at synapses (Thomas et al. 2005; tions comprising a(2-6) and b(2-4). The a7 and Trillerand Choquet 2005; Bogdanovet al. 2006). a9 subunits can form homomers but also com- Many of these interactions are regulated bine with other subunits, such as a10 (a9a10) by phosphorylation of receptor subunits and or b2(a7b2). The less-extensive 5-HT3Rfamily their associated molecules, affecting receptor forms cation-permeable channels from only two trafficking, assembly, and stability in the surface main subunits, 5-HT3A and 5-HT3B.The5-HT3A membrane. Consensus sites for serine/threo- subunit either forms homomers or coassembles nine and tyrosine kinase phosphorylation of with 5-HT3B. Three other subunits have been re- GABAA/CR and GlyR subunits are located in ported—5-HT3C–E —but these primarily affect the intracellular domains between M3 and M4 the expression levels of 5-HT3A and not the re- of GABAAR a4, b-, and g-subunits, and GlyR ceptor’s physiological profile (Alexander et al. a-subunits (Moss and Smart 1996). Gephyrin 2008). can also be phosphorylated, which is important for inhibitory synaptic plasticity (Tyagarajan and Fritschy 2010). Anchoring Cys-Loop Receptors: With regard to clustering nAChRs in skeletal Receptor-Associated Molecules and muscle, rapsyn plays a major role with the re- Phosphorylation ceptor tyrosine kinase, MuSK, linking via b- The efficacy of synaptic transmission relies heavi- catenin and b-dystroglycan to form a scaffold ly on receptor subunit composition and the between nAChRs and the cytoskeleton (Bru- numbers that cluster opposite axon terminals. neau et al. 2009). For neuronal nAChRs, al- Receptor-associated molecules provide a scaf- though receptor-associated