Modeling and Mutational Analysis of the Binding Mode for the Multimodal Antidepressant Drug Vortioxetine to the Human 5-HT3A Receptor.

Abstract:

:5-Hydroxytryptamine3 (5-HT3) receptors are ligand-gated ion channels that mediate neurotransmission by serotonin in the central nervous system. Pharmacological inhibition of 5-HT3 receptor activity has therapeutic potential in several psychiatric diseases, including depression and anxiety. The recently approved multimodal antidepressant vortioxetine has potent inhibitory activity at 5-HT3 receptors. Vortioxetine has an inhibitory mechanism that differs from classic 5-HT3 receptor competitive antagonists despite being believed to bind in the same binding site. Specifically, vortioxetine shows partial agonist activity followed by persistent and insurmountable inhibition. We have investigated the binding mode of vortioxetine at the human 5-HT3A receptor through computational and in vitro experiments to provide insight into the molecular mechanisms behind the unique pharmacological profile of the drug. We find that vortioxetine binds in a manner different from currently known 5-HT3A orthosteric ligands. Specifically, while the binding pattern of vortioxetine mimics some aspects of both the setron class of competitive antagonists and 5-hydroxytryptamine (5-HT) with regards to interactions with residues of the aromatic box motif in the orthosteric binding site, vortioxetine also forms interactions with residues not previously described to be important for the binding of either setrons or 5-HT such as Val202 on Loop F. Our results expand the framework for understanding how orthosteric ligands drive 5-HT3 receptor function, which is of importance for the potential future development of novel classes of 5-HT3 receptor antagonists.

journal_name

Mol Pharmacol

journal_title

Molecular pharmacology

authors

Ladefoged LK,Munro L,Pedersen AJ,Lummis SCR,Bang-Andersen B,Balle T,Schiøtt B,Kristensen AS

doi

10.1124/mol.118.113530

subject

Has Abstract

pub_date

2018-12-01 00:00:00

pages

1421-1434

issue

6

eissn

0026-895X

issn

1521-0111

pii

mol.118.113530

journal_volume

94

pub_type

杂志文章
  • Selective cytotoxicity of haloethylnitrosoureas in a carcinoma cell line resistant to bifunctional nitrogen mustards.

    abstract::A Walker 256 rat carcinoma cell line (WR) has been shown to be resistant to a broad spectrum of bifunctional nitrogen mustards (NM) in cell culture. The parent cell line (WS) from which the WR cells were selected retains marked sensitivity to this class of drugs. Karyotype analysis showed that the parent WS had a chro...

    journal_title:Molecular pharmacology

    pub_type: 杂志文章

    doi:

    authors: Tew KD,Wang AL

    更新日期:1982-05-01 00:00:00

  • Induction of aggregation and augmentation of protein kinase-mediated phosphorylation of purified vimentin intermediate filaments by withangulatin A.

    abstract::Purified assembly-competent vimentin, an intermediate filament protein, was obtained from bovine lens in this study. The effects of withangulatin A on vimentin assembly with or without phosphorylation were examined by negative-stain electron microscopy. Soluble tetrameric vimentin was assembled into irregular fibrils ...

    journal_title:Molecular pharmacology

    pub_type: 杂志文章

    doi:

    authors: Perng MD,Cheng TJ,Chen CM,Lai YK

    更新日期:1994-10-01 00:00:00

  • Does the Lipid Bilayer Orchestrate Access and Binding of Ligands to Transmembrane Orthosteric/Allosteric Sites of G Protein-Coupled Receptors?

    abstract::The ligand-binding sites of many G protein-coupled receptors (GPCRs) are situated around and deeply embedded within the central pocket formed by their seven transmembrane-spanning α-helical domains. Generally, these binding sites are assumed accessible to endogenous ligands from the aqueous phase. Recent advances in t...

    journal_title:Molecular pharmacology

    pub_type: 杂志文章,评审

    doi:10.1124/mol.118.115113

    authors: Szlenk CT,Gc JB,Natesan S

    更新日期:2019-11-01 00:00:00

  • Identification of the multidrug resistance-related P-glycoprotein as a cyclosporine binding protein.

    abstract::The immunosuppressive agent cyclosporine A has been shown to reverse multidrug resistance (MDR) in malignant cells. In the present study, a 3H-cyclosporine diazirine analogue was used to photolabel viable MDR Chinese hamster ovary cells. The 170-kDa membrane P-glycoprotein, which functions as a drug efflux pump, was s...

    journal_title:Molecular pharmacology

    pub_type: 杂志文章

    doi:

    authors: Foxwell BM,Mackie A,Ling V,Ryffel B

    更新日期:1989-10-01 00:00:00

  • A Latin American Perspective on G Protein-Coupled Receptors.

    abstract::G protein-coupled receptors are sensors that interact with a large variety of elements, including photons, ions, and large proteins. Not surprisingly, these receptors participate in the numerous normal physiologic processes that we refer to as health and in its perturbations that constitute disease. It has been estima...

    journal_title:Molecular pharmacology

    pub_type:

    doi:10.1124/mol.116.106062

    authors: Pupo AS,García-Sáinz JA

    更新日期:2016-11-01 00:00:00

  • Sirtuin 1 Mediates the Actions of Peroxisome Proliferator-Activated Receptor δ on the Oxidized Low-Density Lipoprotein-Triggered Migration and Proliferation of Vascular Smooth Muscle Cells.

    abstract::Peroxisome proliferator-activated receptor δ (PPARδ) has been implicated in vascular pathophysiology. However, its functions in atherogenic changes of the vascular wall have not been fully elucidated. PPARδ activated by GW501516 (2-[2-methyl-4-[[4-methyl-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl]methylsulfanyl]ph...

    journal_title:Molecular pharmacology

    pub_type: 杂志文章

    doi:10.1124/mol.116.104679

    authors: Hwang JS,Ham SA,Yoo T,Lee WJ,Paek KS,Lee CH,Seo HG

    更新日期:2016-11-01 00:00:00

  • Thapsigargin induces expression of activating transcription factor 3 in human keratinocytes involving Ca2+ ions and c-Jun N-terminal protein kinase.

    abstract::Thapsigargin is a specific inhibitor of the sarco/endoplasmic reticulum Ca(2+) ATPase of the endoplasmic reticulum. Here, we show that stimulation of human HaCaT keratinocytes with nanomolar concentrations of thapsigargin triggers expression of activating transcription factor (ATF) 3, a basic-region leucin zipper tran...

    journal_title:Molecular pharmacology

    pub_type: 杂志文章

    doi:10.1124/mol.110.067637

    authors: Spohn D,Rössler OG,Philipp SE,Raubuch M,Kitajima S,Griesemer D,Hoth M,Thiel G

    更新日期:2010-11-01 00:00:00

  • Molecular basis of the synergistic inhibition of platelet function by nitrovasodilators and activators of adenylate cyclase: inhibition of cyclic AMP breakdown by cyclic GMP.

    abstract::We investigated the roles of cyclic GMP and cyclic AMP in the inhibition of rabbit platelet aggregation and degranulation by two nitrovasodilators, sodium nitroprusside (SNP) and 3-morpholinosydnonimine (SIN-1; the active metabolite of molsidomine), with particular reference to the synergistic interaction of these dru...

    journal_title:Molecular pharmacology

    pub_type: 杂志文章

    doi:

    authors: Maurice DH,Haslam RJ

    更新日期:1990-05-01 00:00:00

  • Effect of avermectin B1a on chick neuronal gamma-aminobutyrate receptor channels expressed in Xenopus oocytes.

    abstract::Chick brain mRNA was isolated and injected into Xenopus oocytes. This led to the expression of gamma-aminobutyrate (GABA) channels easily accessible for current measurements using the voltage clamp technique. The effect of the anthelmintic natural product avermectin B1a on the GABA current was studied quantitatively. ...

    journal_title:Molecular pharmacology

    pub_type: 杂志文章

    doi:

    authors: Sigel E,Baur R

    更新日期:1987-12-01 00:00:00

  • Quantification of functional selectivity at the human α(1A)-adrenoceptor.

    abstract::Although G protein-coupled receptors are often categorized in terms of their primary coupling to a given type of Gα protein subunit, it is now well established that many show promiscuous coupling and activate multiple signaling pathways. Furthermore, some agonists selectively activate signaling pathways by promoting i...

    journal_title:Molecular pharmacology

    pub_type: 杂志文章

    doi:10.1124/mol.110.067454

    authors: Evans BA,Broxton N,Merlin J,Sato M,Hutchinson DS,Christopoulos A,Summers RJ

    更新日期:2011-02-01 00:00:00

  • Exposure to diethylstilbestrol during pregnancy modulates microRNA expression profile in mothers and fetuses reflecting oncogenic and immunological changes.

    abstract::Prenatal exposure to diethylstilbestrol (DES) is known to cause an increased susceptibility to a wide array of clinical disorders in humans. Previous studies from our laboratory demonstrated that prenatal exposure to DES induces thymic atrophy and apoptosis in the thymus. In the current study, we investigated if such ...

    journal_title:Molecular pharmacology

    pub_type: 杂志文章

    doi:10.1124/mol.114.096743

    authors: Singh NP,Abbas IK,Menard M,Singh UP,Zhang J,Nagarkatti P,Nagarkatti M

    更新日期:2015-05-01 00:00:00

  • Ceramide 1-Phosphate Increases P-Glycoprotein Transport Activity at the Blood-Brain Barrier via Prostaglandin E2 Signaling.

    abstract::P-glycoprotein, an ATP-driven efflux pump, regulates permeability of the blood-brain barrier (BBB). Sphingolipids, endogenous to brain tissue, influence inflammatory responses and cell survival in vitro. Our laboratory has previously shown that sphingolipid signaling by sphingosine 1-phosphate decreases basal P-glycop...

    journal_title:Molecular pharmacology

    pub_type: 杂志文章

    doi:10.1124/mol.116.107169

    authors: Mesev EV,Miller DS,Cannon RE

    更新日期:2017-04-01 00:00:00

  • Discovery of an ectopic activation site on the M(1) muscarinic receptor.

    abstract::Receptors have well-conserved regions that are recognized and activated by hormones and neurotransmitters. Most drugs bind to these sites and mimic or block the action of the native ligands. Using a high-throughput functional screen, we identified a potent and selective M(1) muscarinic receptor agonist from a novel st...

    journal_title:Molecular pharmacology

    pub_type: 杂志文章

    doi:10.1124/mol.61.6.1297

    authors: Spalding TA,Trotter C,Skjaerbaek N,Messier TL,Currier EA,Burstein ES,Li D,Hacksell U,Brann MR

    更新日期:2002-06-01 00:00:00

  • Intracellular domains of NR2 alter calcium-dependent inactivation of N-methyl-D-aspartate receptors.

    abstract::At central excitatory synapses, the transient elevation of intracellular calcium reduces N-methyl-D-aspartate (NMDA) receptor activity. Such 'calcium-dependent inactivation' is mediated by interactions of calcium/calmodulin and alpha-actinin with the C terminus of NMDA receptor 1 (NR1) subunit. However, inactivation i...

    journal_title:Molecular pharmacology

    pub_type: 杂志文章

    doi:10.1124/mol.61.3.595

    authors: Vissel B,Krupp JJ,Heinemann SF,Westbrook GL

    更新日期:2002-03-01 00:00:00

  • Multiple conformations of native and recombinant human 5-hydroxytryptamine(2a) receptors are labeled by agonists and discriminated by antagonists.

    abstract::We have expanded previous studies with the 5-hydroxytryptamine (5-HT)(2) receptor agonist (+/-)-1-(2,5-dimethoxy-4-[(125)I]iodophenyl)-2-aminopropane [(+/-)-[(125)I]DOI] in human brain that had shown biphasic competition curves for several 5-HT(2A) receptor antagonists by using new selective antagonists of 5-HT(2A) (M...

    journal_title:Molecular pharmacology

    pub_type: 杂志文章

    doi:

    authors: López-Giménez JF,Villazón M,Brea J,Loza MI,Palacios JM,Mengod G,Vilaró MT

    更新日期:2001-10-01 00:00:00

  • A crucial role for the mitogen-activated protein kinase pathway in nicotinic cholinergic signaling to secretory protein transcription in pheochromocytoma cells.

    abstract::The mitogen-activated protein kinase (MAPK) pathway plays a pivotal role in intracellular signaling, and this cascade may impinge on cAMP response elements (CREs) of target genes. Both the MAPK pathway and chromogranin A expression may be activated by cytosolic calcium influx, and calcium-dependent signals map onto th...

    journal_title:Molecular pharmacology

    pub_type: 杂志文章

    doi:10.1124/mol.54.1.59

    authors: Tang K,Wu H,Mahata SK,O'Connor DT

    更新日期:1998-07-01 00:00:00

  • Ion movements in isolated bovine adrenal medullary cells treated with ouabain.

    abstract::In the previous paper [Mol. Pharmacol. 23:671-680 (1983)] it was shown that ouabain enhances the exocytotic release of catecholamines from isolated bovine adrenal medullary cells. This effect is dependent upon extracellular sodium, but persists in the nominal absence of calcium. In this paper the study has been extend...

    journal_title:Molecular pharmacology

    pub_type: 杂志文章

    doi:

    authors: Pocock G

    更新日期:1983-05-01 00:00:00

  • Selective up-regulation of alpha1a-adrenergic receptor protein and mRNA in brown adipose tissue by neural and beta3-adrenergic stimulation.

    abstract::Previous studies have shown that neural stimulation of brown adipose tissue (BAT) reorganizes the expression and activity of signaling proteins in the beta-adrenergic adenylyl cyclase pathway. Cold stress increases neural stimulation of BAT and increases alpha1-adrenergic receptor number; however, the alpha1 receptor ...

    journal_title:Molecular pharmacology

    pub_type: 杂志文章

    doi:10.1124/mol.51.4.644

    authors: Granneman JG,Zhai Y,Lahners KN

    更新日期:1997-04-01 00:00:00

  • Clonidine-displacing substance from bovine brain binds to imidazoline receptors and releases catecholamines in adrenal chromaffin cells.

    abstract::Identification of nonadrenergic binding sites for clonidine and related imidazolines in brain and peripheral tissues and partial purification of an endogenous ligand for these sites have led to the postulation of a novel transmitter/receptor system. The receptors seem to be present in adrenal medulla and to regulate c...

    journal_title:Molecular pharmacology

    pub_type: 杂志文章

    doi:

    authors: Regunathan S,Meeley MP,Reis DJ

    更新日期:1991-12-01 00:00:00

  • Effects of n-dodecylguanidine on A-type potassium channels: role of external surface charges in channel gating.

    abstract::n-Dodecylguanidine (C12-G) is an amphipathic compound with a guanidine moiety, which is positively charged at physiological pH, and a hydrophobic side chain. Its effects on an A-type K+ channel clone (rKv1.4) expressed in Xenopus oocytes were examined. C12-G caused a concentration-dependent (1-20 microM) positive shif...

    journal_title:Molecular pharmacology

    pub_type: 杂志文章

    doi:

    authors: Yao JA,Saxena NC,Ziai MR,Ling S,Tseng GN

    更新日期:1995-07-01 00:00:00

  • Functional selectivity of orphanin FQ for its receptor coexpressed with potassium channel subunits in Xenopus laevis oocytes.

    abstract::An opioid-like receptor has been cloned by several groups of researchers and recently shown to be activated by an endogenous heptadecapeptide termed orphanin FQ (or nociceptin). We isolated the corresponding mouse cDNA and coexpressed it in Xenopus laevis oocytes with the potassium channel subunits Kir3.1 (GIRK1) and ...

    journal_title:Molecular pharmacology

    pub_type: 杂志文章

    doi:

    authors: Matthes H,Seward EP,Kieffer B,North RA

    更新日期:1996-09-01 00:00:00

  • Mechanisms influencing stimulatory effects of spermine at recombinant N-methyl-D-aspartate receptors.

    abstract::Stimulatory effects of spermine at heteromeric N-methyl-D-aspartate (NMDA) receptors expressed from cloned subunits were studied by voltage-clamp recording in Xenopus oocytes. At NR1A/NR2B receptors, in the presence of a saturating concentration of glycine, the magnitude of spermine stimulation was dependent on the co...

    journal_title:Molecular pharmacology

    pub_type: 杂志文章

    doi:

    authors: Williams K

    更新日期:1994-07-01 00:00:00

  • Isolation and purification of rat liver morphine UDP-glucuronosyltransferase.

    abstract::A UDP-glucuronosyltransferase (UDPGT) isoenzyme capable of morphine glucuronidation has been purified to apparent homogeneity and partially characterized from hepatic microsomes of female Wistar rats which have low 3 alpha-hydroxysteroid UDPGT. A rapid and sensitive assay was developed to quantify morphine glucuronide...

    journal_title:Molecular pharmacology

    pub_type: 杂志文章

    doi:

    authors: Puig JF,Tephly TR

    更新日期:1986-12-01 00:00:00

  • Kinetic studies of [3H]-N-methylscopolamine binding to muscarinic receptors in the rat central nervous system: evidence for the existence of three classes of binding sites.

    abstract::We compared the binding of [N-methyl-3H]scopolamine methyl chloride [( 3H]NMS) and pirenzepine to muscarinic receptors in four regions of the rat central nervous system (cortex, hippocampus, striatum, and cerebellum) and in rat heart. Equilibrium binding studies suggested the existence of three classes of receptors: A...

    journal_title:Molecular pharmacology

    pub_type: 杂志文章

    doi:

    authors: Waelbroeck M,Gillard M,Robberecht P,Christophe J

    更新日期:1986-10-01 00:00:00

  • Insulin-like growth factor type-I receptor-dependent phosphorylation of extracellular signal-regulated kinase 1/2 but not Akt (protein kinase B) can be induced by picropodophyllin.

    abstract::The initial event upon binding of insulin-like growth factor 1 to the insulin-like growth factor type-I receptor (IGF-1R) is auto-phosphorylation of tyrosine residues within the activation loop of the kinase domain followed by phosphorylation of other receptor tyrosine residues and the subsequent activation of the int...

    journal_title:Molecular pharmacology

    pub_type: 杂志文章

    doi:10.1124/mol.107.040014

    authors: Vasilcanu R,Vasilcanu D,Sehat B,Yin S,Girnita A,Axelson M,Girnita L

    更新日期:2008-03-01 00:00:00

  • DNA damage effects of a polyamide-CBI conjugate in SV40 virions.

    abstract::Polyamides are a class of synthetic molecules that exhibit high-affinity, sequence-specific reversible binding in the DNA minor groove but are incapable of inducing DNA damage. In cell-free systems, polyamides have been shown to regulate gene expression by activation, repression, and antirepression. However, effective...

    journal_title:Molecular pharmacology

    pub_type: 杂志文章

    doi:10.1124/mol.104.006254

    authors: Philips BJ,Chang AY,Dervan PB,Beerman TA

    更新日期:2005-03-01 00:00:00

  • G Protein-Coupled Receptor Endocytosis Confers Uniformity in Responses to Chemically Distinct Ligands.

    abstract::The ability of chemically distinct ligands to produce different effects on the same G protein-coupled receptor (GPCR) has interesting therapeutic implications, but, if excessively propagated downstream, would introduce biologic noise compromising cognate ligand detection. We asked whether cells have the ability to lim...

    journal_title:Molecular pharmacology

    pub_type: 杂志文章

    doi:10.1124/mol.116.106369

    authors: Tsvetanova NG,Trester-Zedlitz M,Newton BW,Riordan DP,Sundaram AB,Johnson JR,Krogan NJ,von Zastrow M

    更新日期:2017-02-01 00:00:00

  • Inhibition of cyclic AMP-dependent kinase by expression of a protein kinase inhibitor/enhanced green fluorescent fusion protein attenuates angiotensin II-induced type 1 AT1 receptor mRNA down-regulation in vascular smooth muscle cells.

    abstract::Expression of the angiotensin II type 1 receptor (AT1-R) mRNA in vascular smooth muscle cells (VSMC) is down-regulated by a variety of agonists, including growth factors, agonists of Galphaq protein-coupled receptors, and activators of adenylyl cyclase. To determine whether cAMP-dependent protein kinases (PKA) partici...

    journal_title:Molecular pharmacology

    pub_type: 杂志文章

    doi:10.1124/mol.54.3.514

    authors: Wang X,Murphy TJ

    更新日期:1998-09-01 00:00:00

  • A New Paroxetine-Based GRK2 Inhibitor Reduces Internalization of the μ-Opioid Receptor.

    abstract::G protein-coupled receptor (GPCR) kinases (GRKs) play a key role in terminating signals initiated by agonist-bound GPCRs. However, chronic stimulation of GPCRs, such as that which occurs during heart failure, leads to the overexpression of GRKs and maladaptive downregulation of GPCRs on the cell surface. We previously...

    journal_title:Molecular pharmacology

    pub_type: 杂志文章

    doi:10.1124/mol.119.118661

    authors: Bouley RA,Weinberg ZY,Waldschmidt HV,Yen YC,Larsen SD,Puthenveedu MA,Tesmer JJG

    更新日期:2020-06-01 00:00:00

  • Prostaglandin-induced activation of nociceptive neurons via direct interaction with transient receptor potential A1 (TRPA1).

    abstract::Inflammation contributes to pain hypersensitivity through multiple mechanisms. Among the most well characterized of these is the sensitization of primary nociceptive neurons by arachidonic acid metabolites such as prostaglandins through G protein-coupled receptors. However, in light of the recent discovery that the no...

    journal_title:Molecular pharmacology

    pub_type: 杂志文章

    doi:10.1124/mol.107.040832

    authors: Taylor-Clark TE,Undem BJ,Macglashan DW Jr,Ghatta S,Carr MJ,McAlexander MA

    更新日期:2008-02-01 00:00:00