Understanding the Bases of Function and Modulation of α7 ...· Nicotinic Receptors: Implications

download Understanding the Bases of Function and Modulation of α7 ...· Nicotinic Receptors: Implications

of 12

  • date post

    18-Jul-2019
  • Category

    Documents

  • view

    217
  • download

    0

Embed Size (px)

Transcript of Understanding the Bases of Function and Modulation of α7 ...· Nicotinic Receptors: Implications

  • 1521-0111/90/3/288299$25.00 http://dx.doi.org/10.1124/mol.116.104240MOLECULAR PHARMACOLOGY Mol Pharmacol 90:288299, September 2016Copyright 2016 by The American Society for Pharmacology and Experimental Therapeutics

    MINIREVIEWA LATIN AMERICAN PERSPECTIVE ON ION CHANNELS

    Understanding the Bases of Function and Modulation of a7Nicotinic Receptors: Implications for Drug Discovery

    Jeremas Corradi and Cecilia BouzatInstituto de Investigaciones Bioqumicas de Baha Blanca, Universidad Nacional del Sur, CONICET/UNS, Baha Blanca,Argentina

    Received March 7, 2016; accepted May 5, 2016

    ABSTRACTThe nicotinic acetylcholine receptor (nAChR) belongs to asuperfamily of pentameric ligand-gated ion channels involvedin many physiologic and pathologic processes. Among nAChRs,receptors comprising the a7 subunit are unique because of theirhigh Ca21 permeability and fast desensitization. nAChR agonistselicit a transient ion flux response that is further sustained by therelease of calcium from intracellular sources. Owing to the dualionotropic/metabotropic nature of a7 receptors, signaling path-ways are activated. The a7 subunit is highly expressed in thenervous system, mostly in regions implicated in cognition andmemory and has therefore attracted attention as a novel drugtarget. Additionally, its dysfunction is associated with severalneuropsychiatric and neurologic disorders, such as schizophre-nia and Alzheimers disease. a7 is also expressed in non-neuronal

    cells, particularly immune cells, where it plays a role in immunity,inflammation, and neuroprotection. Thus, a7 potentiation hasemerged as a therapeutic strategy for several neurologic andinflammatory disorders. With unique activation properties, thereceptor is a sensitive drug target carrying different potentialbinding sites for chemical modulators, particularly agonists andpositive allosteric modulators. Although macroscopic and single-channel recordings have provided significant information aboutthe underlying molecular mechanisms and binding sites of mod-ulatory compounds, we know just the tip of the iceberg. Furtherconcerted efforts are necessary to effectively exploit a7 as a drugtarget for each pathologic situation. In this article, we focusmainlyon the molecular basis of activation and drug modulation of a7,key pillars for rational drug design.

    IntroductionNicotine has been a key molecule for the advancement of

    pharmacology since the beginning of the 20th century, whenLangley (1905), through fundamental experiments, concludedthat muscle contraction was mediated by a receptive sub-stance present on the muscle. The muscle nicotinic acetylcho-line receptor (nAChR) was thus a pillar in the discovery ofneurotransmitter receptors (Langley, 1905). Still, it was not until1970 that the first neurotransmitter receptor, nAChR, wasidentified (Changeux et al., 1970;Miledi and Potter, 1971).Withthe later advent of themolecular biology revolution in the 1980s,the nAChR family was first identified and an extended family ofhomologous pentameric receptors was revealed (Patrick et al.,

    1983; Le Novre and Changeux, 1995). This class of receptorswas first known as Cys-loop receptors because all family sub-units contain a conserved pair of disulfide-bonded cysteinesseparated by 13 residues. The discovery of orthologs in pro-karyotes (Tasneem et al., 2005), which lack the double cyste-ines, has extended the Cys-loop family to the superfamily ofpentameric ligand-gated ion channels (pLGIC).In vertebrates, the pLGIC superfamily includes cationic chan-

    nels, nAChRs and serotonin 5-HT3 receptors, and anionic chan-nels activated by GABA or glycine (Le Novre and Changeux,2001; Lester et al., 2004; Sine andEngel, 2006;Bartos et al., 2009).Their vital role in converting chemical recognition into anelectrical impulse makes these receptors prime loci for learn-ing, memory, and disease processes, as well as targets for clini-cally relevant drugs.The nAChR is widely distributed throughout the animal

    kingdom, from nematodes to humans (LeNovre and Changeux,1995). nAChRs are expressed in many regions of the central

    This work was supported by grants from Universidad Nacional del Sur(UNS), Consejo Nacional de Investigaciones Cientficas y Tcnicas (CONI-CET), FONCYT, and the Bill and Melinda Gates Foundation to C.B.

    dx.doi.org/10.1124/mol.116.104240.

    ABBREVIATIONS: ACh, acetylcholine; a-BTX, a-bungarotoxin; ECD, extracellular domain; JAK, Janus kinase; LY-2087101, (2-amino-5-keto)thiazole), [2-[(4-fluorophenyl)amino]-4-methyl-5-thiazolyl]-3-thienyl-methanone; nAChR, nicotinic acetylcholine receptor; NAM, negative allostericmodulators; NS-1738, 1-(5-chloro-2-hydroxyphenyl)-3-(2-chloro-5-trifluoromethylphenyl)urea; PAM, positive allosteric modulator; pLGIC, pentamericligand-gated ion channels; PNU-120596, 1-(5-chloro-2,4-dimethoxyphenyl)-3-(5-methylisoxazol-3-yl)urea; SAM, silent allosteric modulator;STAT, signal transducer and activator of transcription; TMD, transmembrane domain; TQS, 4-(naphthalen-1-yl)-3a,4,5,9b-tetrahydro-3H-cyclopenta[c]quinoline-8-sulfonamide.

    288

    at ASPE

    T Journals on July 17, 2019

    molpharm

    .aspetjournals.orgD

    ownloaded from

    http://dx.doi.org/10.1124/mol.116.104240http://dx.doi.org/10.1124/mol.116.104240http://molpharm.aspetjournals.org/
  • and peripheral nervous system, in addition to non-neuronaltissues. The muscle nAChR plays a major role in neuromus-cular transmission and is the target of muscle relaxants (Sine,2012), whereas nAChRs in the brain represent a broad hetero-geneous family of ubiquitously expressed receptors. nAChRresponses to endogenous acetylcholine (Ach) and choline andexogenous nicotine are involved in a number of physiologicprocesses and pharmacological effects (Dani and Bertrand,2007; Albuquerque et al., 2009; Hurst et al., 2013).The homopentameric a7, one of the most abundant nAChRs

    in the nervous system, is also expressed inmany non-neuronalcells. Its unique activation properties, high calcium perme-ability, ionotropic/metabotropic dual action, ubiquitous distri-bution, and involvement in a range of neurologic, psychiatric,and inflammatory disorders have made a7 an importantemerging drug target; the participation of a7 in pathologicconditions and the therapeutic potential of a7 ligands has beenwell documented (see for example Taly and Changeux, 2008;Wallace and Porter, 2011; Lendvai et al., 2013; Wallace andBertrand, 2013; Uteshev, 2014; Dineley et al., 2015). In thisarticle, we focus on the unique properties of activation and drugmodulation of a7 and its relationship with disease and therapy.

    nAChR Structure and FunctionnAChR subunits are classified as two types, a and non-a,

    with the a-type containing a disulfide bridge in the agonistbinding site. Five muscular (a1, b, g, , and d) and elevenneuronal (a2a7, a9, a10, and b2b4) nAChR subunits havebeen identified in the mammalian genome (ligand-gatedion channel database, http://www.ebi.ac.uk/compneur-srv/LGICdb/cys-loop.php).nAChRs are assembled from five identical (a7 or a9) or

    different subunits (at least two a-type subunits), and can formavariety of different heteromeric receptors with a broad spec-trum of pharmacological and kinetic properties (Fig. 1). Theresolution of the three-dimensional structures of pLGICs hasbeen the subject of intense efforts over the last decade (Brejcet al., 2001; Dellisanti et al., 2007; Hilf andDutzler, 2008, 2009;Bocquet et al., 2009; Hibbs and Gouaux, 2011; Corringer et al.,2012; Hassaine et al., 2014; Miller and Aricescu, 2014; Sauguetet al., 2014; Cecchini and Changeux, 2015). However, no high-resolution structure of the full length a7 has been reported todate; an extracellular domain of a7/AChBP chimera (Li et al.,2011; Nemecz and Taylor, 2011) and a nuclear magneticresonance (NMR) structure of a7 transmembrane domain havebeen described (Bondarenko et al., 2014).All pLGICs share a conserved organization with five

    subunits symmetrically arranged around a central ion pore(Fig. 2). Functional domains include the extracellular domain(ECD), which carries the agonist binding sites at subunitinterfaces; the transmembrane domain (TMD), which con-tains the ion pore and the gate; and the intracellular domain(ICD), which contains determinants of channel conductanceand sites for regulation and intracellular signaling (Pauloet al., 2009; Jones et al., 2010; King et al., 2015) (Fig. 2). Theinterface between the ECD and TMD, also referred to as thecoupling region, is important for coupling agonist binding tochannel opening (Bouzat et al., 2004; Lee and Sine, 2005;Castillo et al., 2006; Bartos et al., 2009), as well as fordetermining open channel lifetime and rate of desensitization(Bouzat et al., 2008; Yan et al., 2015) (Fig. 2).

    The possible structural events that translate neurotrans-mitter binding at the ECD into opening of the transmembraneion channel 60 away is an issue of intense research that hasbeen discussed in recent reviews (Corringer et al., 2012;Althoff et al., 2014; Sauguet et al., 2014; Cecchini and Changeux,2015). On the basis of the Monod-Wyman-Changeux model(Monod et al., 1965), the functional response of a pLGIC can beinterpreted as a selection from a few global and discreteconformations elicited by the binding of agonist: closed, open,and desensitized, the latter showing high agonist affinity at thesame time being impermeable to ions (Zhang et al., 2013) (Fig. 3).Intermediate states between closed and open or open anddesensitized states have been proposed for nAChRs and severalpLGICs (Lape et al., 2008; Corradi et al., 2009; Mukhtasimovaet al., 2009; Cecchini and Changeux, 2015). Therefore, thenumber of states in the main conformations and the rate oftransition between states determine receptor kinetics, and thistunes each receptor to its physiologic role. In turn, drugs, bybinding to different stat