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Modulating Inhibitory Ligand-Gated Ion Channels

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Modulating Inhibitory Ligand-Gated Ion Channels The AAPS Journal 2006; 8 (2) Article 40 (http://www.aapsj.org). Themed Issue: Drug Addiction - From Basic Research to Therapies Guest Editors - Rao Rapaka and Wolfgang Sadée Modulating Inhibitory Ligand-Gated Ion Channels Submitted: March 3 , 2006 ; Accepted: March 29 , 2006 ; Published: May 26, 2006 Michael Cascio1 1 Department of Molecular Genetics and Biochemistry, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261 A BSTRACT tors is unavoidable since the structure of a soluble acetyl- choline binding protein (AChBP) that is a homolog of the The glycine and ␥ -aminobutyric acid receptors (GlyR extracellular domain (ECD) of nicotinicoid receptors has and GABA R, respectively) are the major inhibitory neu- A been resolved in crystallographic studies,3 rotransmitter-gated receptors in the central nervous system and the structure of isolated nAChR from Torpedo has been resolved by of animals. Given the important role of these receptors in 4 neuronal inhibition, they are prime targets of many thera- cryomicroscopy to 4 Å. These structures provide an appro- peutic agents and are the object of intense studies aimed priate template for modeling all nicotinicoid receptors and have been extensively used by investigators to interpret and at correlating their structure and function. In this review, 5 the structure and dynamics of these and other homologous refi ne our understanding of these receptors. members of the nicotinicoid superfamily are described. The Both GlyR and GABAA R are channels whose role in the modulatory actions of the major biological macromolecules central nervous system (CNS) of adults is to mediate inhi b- that bind and allosterically affect these receptors are also itory neurotransmission by facilitating Cl- infl ux into discussed. neurons. 6 , 7 Each receptor type has a distinctive tissue distri- bution, with GlyRs being the primary target for inhibitory neurotransmission in the brainstem and spinal cord and K EYWORDS: Glycine receptor , GABAA receptor , nicotinicoid , anesthetics , therapeutics GABA A Rs being more widely distributed throughout the CNS. However, mixed GABA-Gly synapses have been observed in many cell types.8-11 For example, both receptor I NTRODUCTION types are found in the retina, where they function in rod photoreceptor development.12 While the specifi c subunit The nicotinicoid receptors are a superfamily of ligand-gated composition of each receptor type may vary spatially and ion channels that are essential mediators of fast neurotrans- temporally, the inhibitory activities of the subtypes of both mission at neuronal and neuromuscular synapses. In verte- receptor classes are broadly similar. Typically, the multiple brates, the major members of this ionotropic superfamily binding of agonists results in rapid channel opening, and include the inhibitory receptors gated by glycine or prolonged ligand occupancy gives rise to receptor desensi- ␥ - aminobutyric acid (GlyR and GABA R, respectively) A tization, a relatively long-lived state that is refractory to and the excitatory receptors gated by acetylcholine or sero- channel reactivation. Complex functional profi les of the tonin (nAChR and 5HT R, respectively). These receptors 3 receptors are generated by differential expression of sub- are assemblies arranged about a central pore that transiently types and altered activities via subunit-specifi c allosteric opens upon the binding of agonist, allowing the passive dif- modulation of the receptors (described below). Hence, each fusion of anions (GlyR and GABA R) or cations (nAChR A receptor subtype has distinct kinetics, conductance, and sen- and 5HT R). 1 , 2 Each pentameric receptor may be comprised 3 sitivities to ligands, giving rise to receptors ’ exquisite and of different gene products (eg, GlyR is composed of ␣ and differential sensitivities and activities. ␤ subunits) and/or splice variants, mixed at different stoi- chiometries. The specifi c conductance properties of all GlyR and GABA A R are generally described as inhibitory channel types are defi ned by their composition, posttransla- neuroreceptors, because channel opening typically results tional modifi cations, and interaction with different modula- in a hyperpolarizing inward Cl- fl ux. However, in embry- tory ligands. Although this review focuses on the inhibitory onic neurons, the higher intracellular Cl- concentration receptors, some discussion of homologous excitatory recep- - results in Cl effl ux upon GlyR and GABAA R activation and a strong excitatory suprathreshold depolarization that gates Corresponding Author: Michael Cascio, Department of Ca 2+ infl ux and is hypothesized to guide neuronal develop- Molecular Genetics and Biochemistry, University of ment.13 GABA is particularly important, as the hyperpolar- Pittsburgh School of Medicine, Pittsburgh, PA 15261 . izing activity of GABAA R in embryonic neurons provides Tel: (412) 648-9488 ; Fax: (412) 624-1401 ; E-mail: most of the excitatory drive in early development.14 Both [email protected] glycinergic and GABAergic pathways have been shown to E353 The AAPS Journal 2006; 8 (2) Article 40 (http://www.aapsj.org). be crucially involved in establishing early inhibitory net- its structural homology to the ECD of nAChR was confi rmed works. 15 In addition to their roles in neuronal development, in lysine scanning mutagenic studies,26 suggesting that each both receptor types have been implicated in many channelo- ECD comprises a sandwich of ␤ -sheets with very little pathies, as dysfunction of these receptors may lead to dis- ␣ -helix. Furthermore, a chimera containing the AChBP and 16 27 ease. GlyR mutations play a role in diseases associated the pore domain of a 5HT3A R retained activity, showing with a lack of motor control, such as spasticity and startle that the AChBP structure can function as a modular ECD 17-19 diseases. Dysfunction of GABA A R-mediated inhibition for the holoreceptor. The original AChBP crystals were has been implicated in many neurological and psychiatric grown in 4-(2-Hydroxyethyl)piperazine-1-ethanesulfonic conditions, including depression, affective disorders, and acid (HEPES) buffer, and HEPES was observed to bind to the epilepsy.20 , 21 nicotinamide binding site. The molecular details of HEPES GlyR was the fi rst neurotransmitter-gated ion channel iso- binding were consistent with the agonist binding sites of lated from mammals and was originally isolated by affi nity homologous nicotinicoid receptors suggested by experi men- chromatography from rats as an assembly of 48 kD ␣ 1 and tal studies. This structural determination of a homolog of the 58 kD ␤ subunits. 22 While ␣ subunits can form homo- ECD of nicotinicoid receptors has provided an essential oligomers, the stoichiometry of hetero-oligomers has template to allow investigators to rationally model the ligand 28-32 ␣ ␤ 23 ␣ binding domains of these receptors (K. Speranskyi, recently been shown to be 2 1 :3 . To date, 4 different ␣ ␤ M. Cascio, and M. Kurnikova, unpublished data, 2006). subunits ( 1 – 4 ) and a single subunit have been identifi ed. The subunits comprising GABAA Rs are more numerous, For GlyR and GABA A R, the binding sites for agonists and with 19 different gene products among the 8 constituent antagonists reside at the interface between adjacent sub- ␣ ␤ ␥ ␦ ⑀ ␲ ␪ ␳ subunit families, 1 – 6 , 1 – 3 , 1 – 3 , , , , , and 1 – 3 (histori- units, and this binding site is modeled as being defi ned by ␳ cally, GABAA Rs comprising subunits have been referred residues on 3 loops of 1 subunit and 3 loops from its neigh- 23,28 to as GABAC Rs), described to date (for more information, bor. Phylogenetic analysis of animal nicotinicoid recep- including sequence alignments, see the Cys-loop Ligand- tors and their prokaryotic homologs (with unknown agonist Gated Ion Channel database at http://www.ebi.ac.uk/ specifi city) indicated that at least 1 aromatic residue is compneur-srv/LGICdb/LGICdb/cys-loop.php24 ). The ma - involved in ligand binding, with cation-pi interactions ␣ ␤ ␥ 33 jority of GABA A Rs contain , , and subunits with a implicated in binding interactions. GlyRs are gated by probable stoichiometry of 2␣ :2 ␤ :1␥ , with the ␣ and ␤ sub- glycine, and ␤ -alanine and taurine are considered partial units necessary for GABA activation and the ␥ subunits agonists. Strychnine is a selective competitive antagonist required for benzodiazepine sensitivity.25 exhibiting the greatest potency toward most GlyR isoforms. For GABA A R, the preferred agonist is GABA, but the receptors are also activated by muscimol and antagonized N ICOTINICOID RECEPTOR TOPOLOGY by benzodiazepines (described in more detail below). Both AND STRUCTURE receptors may be gated by ␤ -alanine and taurine,34 and tau- rine plays an important role as agonist for either receptor in For both types of channels, further structural and functional regions where both are coexpressed.12 The selectivity of diversity is introduced by splice variants. Regardless of agonists for specifi c subunit composition may be exploited composition, all members of the nicotinicoid superfamily, therapeutically. For example, the ␦ -containing GABA R is including the excitatory nAChR and 5HT R cation chan- A 3 highly expressed extrasynaptically in the thalamus and has nels, share a common topology. The pore domain of each a high affi nity for gaboxadol, which has effi cacy as a treat- subunit contains 4 transmembrane (TM) segments, M1 to ment for insomnia.35 Given the homology between GlyR M4, and their connecting loops, with the 5 M2 amphiphilic
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