α-Conotoxins Identify the α3β4* Subtype as the Predominant Nicotinic Acetylcholine Receptor Expressed in Human Adrenal Chromaffin Cells.

Abstract:

:Ligands that selectively inhibit human α3β2 and α6β2 nicotinic acetylcholine receptor (nAChRs) and not the closely related α3β4 and α6β4 subtypes are lacking. Current α-conotoxins (α-Ctxs) that discriminate among these nAChR subtypes in rat fail to discriminate among the human receptor homologs. In this study, we describe the development of α-Ctx LvIA(N9R,V10A) that is 3000-fold more potent on oocyte-expressed human α3β2 than α3β4 and 165-fold more potent on human α6/α3β2β3 than α6/α3β4 nAChRs. This analog was used in conjuction with three other α-Ctx analogs and patch-clamp electrophysiology to characterize the nAChR subtypes expressed by human adrenal chromaffin cells. LvIA(N9R,V10A) showed little effect on the acetylcholine-evoked currents in these cells at concentrations expected to inhibit nAChRs with β2 ligand-binding sites. In contrast, the β4-selective α-Ctx BuIA(T5A,P6O) inhibited >98% of the acetylcholine-evoked current, indicating that most of the heteromeric receptors contained β4 ligand-binding sites. Additional studies using the α6-selective α-Ctx PeIA(A7V,S9H,V10A,N11R,E14A) indicated that the predominant heteromeric nAChR expressed by human adrenal chromaffin cells is the α3β4* subtype (asterisk indicates the possible presence of additional subunits). This conclusion was supported by polymerase chain reaction experiments of human adrenal medulla gland and of cultured human adrenal chromaffin cells that demonstrated prominent expression of RNAs for α3, α5, α7, β2, and β4 subunits and a low abundance of RNAs for α2, α4, α6, and α10 subunits.

journal_name

Mol Pharmacol

journal_title

Molecular pharmacology

authors

Hone AJ,McIntosh JM,Azam L,Lindstrom J,Lucero L,Whiteaker P,Passas J,Blázquez J,Albillos A

doi

10.1124/mol.115.100982

subject

Has Abstract

pub_date

2015-11-01 00:00:00

pages

881-93

issue

5

eissn

0026-895X

issn

1521-0111

pii

mol.115.100982

journal_volume

88

pub_type

杂志文章
  • New sigma-like receptor recognized by novel phenylaminotetralins: ligand binding and functional studies.

    abstract::Several novel phenylaminotetralins (PATs) cause functional changes in brain that are associated with binding to saturable, high affinity sites that are not identical to any known central nervous system receptor. These PATs were tested for their ability to cause receptor-mediated functional effects on tyrosine hydroxyl...

    journal_title:Molecular pharmacology

    pub_type: 杂志文章

    doi:

    authors: Booth RG,Wyrick SD,Baldessarini RJ,Kula NS,Myers AM,Mailman RB

    更新日期:1993-12-01 00:00:00

  • Valproic acid inhibits angiogenesis in vitro and in vivo.

    abstract::Valproic acid (VPA) is a widely used antiepileptic agent that is undergoing clinical evaluation for anticancer therapy. We assessed the effects of VPA on angiogenesis in vitro and in vivo. In human umbilical vein endothelial cells, therapeutically relevant concentrations of VPA (0.25 to 1 mM) inhibited proliferation, ...

    journal_title:Molecular pharmacology

    pub_type: 杂志文章

    doi:10.1124/mol.65.3.520

    authors: Michaelis M,Michaelis UR,Fleming I,Suhan T,Cinatl J,Blaheta RA,Hoffmann K,Kotchetkov R,Busse R,Nau H,Cinatl J Jr

    更新日期:2004-03-01 00:00:00

  • Transforming growth factor-beta 1 down-regulates basal and polycyclic aromatic hydrocarbon-induced cytochromes P-450 1A1 and 1A2 in adult human hepatocytes in primary culture.

    abstract::The effects of interleukin (IL)-1 beta, IL-4, IL-6, tumor necrosis factor (TNF)-alpha, interferon (IFN)-alpha, IFN-gamma, and transforming growth factor (TGF)-beta 1 on cytochrome P-450 (CYP) 1A expression and polycyclic aromatic hydrocarbon (PAH)-mediated induction in primary human hepatocyte cultures were determined...

    journal_title:Molecular pharmacology

    pub_type: 杂志文章

    doi:

    authors: Abdel-Razzak Z,Corcos L,Fautrel A,Campion JP,Guillouzo A

    更新日期:1994-12-01 00:00:00

  • Requirement of Gbetagamma and c-Src in D2 dopamine receptor-mediated nuclear factor-kappaB activation.

    abstract::The D2 dopamine receptor (D2R) was examined for its ability to mediate nuclear factor-kappaB (NF-kappaB) activation through G proteins. Stimulation of D2R-transfected HeLa cells with its agonist quinpirole induced the expression of a NF-kappaB luciferase reporter and formation of NF-kappaB-DNA complex. This response w...

    journal_title:Molecular pharmacology

    pub_type: 杂志文章

    doi:10.1124/mol.64.2.447

    authors: Yang M,Zhang H,Voyno-Yasenetskaya T,Ye RD

    更新日期:2003-08-01 00:00:00

  • Mapping of maurotoxin binding sites on hKv1.2, hKv1.3, and hIKCa1 channels.

    abstract::Maurotoxin (MTX) is a potent blocker of human voltage-activated Kv1.2 and intermediate-conductance calcium-activated potassium channels, hIKCa1. Because its blocking affinity on both channels is similar, although the pore region of these channels show only few conserved amino acids, we aimed to characterize the bindin...

    journal_title:Molecular pharmacology

    pub_type: 杂志文章

    doi:10.1124/mol.104.002774

    authors: Visan V,Fajloun Z,Sabatier JM,Grissmer S

    更新日期:2004-11-01 00:00:00

  • Pharmacological targeting of adipocytes/fat metabolism for treatment of obesity and diabetes.

    abstract::Obesity is now recognized as a rapidly increasing worldwide threat to health, largely as a result of causing diabetes. Thus, considerable efforts are underway in the pharmaceutical industry to find drugs to treat this condition. Target validation in various academic and industrial laboratories has revealed a number of...

    journal_title:Molecular pharmacology

    pub_type: 杂志文章,评审

    doi:10.1124/mol.106.026104

    authors: Pilch PF,Bergenhem N

    更新日期:2006-09-01 00:00:00

  • Pharmacological NAD-Boosting Strategies Improve Mitochondrial Homeostasis in Human Complex I-Mutant Fibroblasts.

    abstract::Mitochondrial disorders are devastating genetic diseases for which efficacious therapies are still an unmet need. Recent studies report that increased availability of intracellular NAD obtained by inhibition of the NAD-consuming enzyme poly(ADP-ribose) polymerase (PARP)-1 or supplementation with the NAD-precursor nico...

    journal_title:Molecular pharmacology

    pub_type: 杂志文章

    doi:10.1124/mol.114.097204

    authors: Felici R,Lapucci A,Cavone L,Pratesi S,Berlinguer-Palmini R,Chiarugi A

    更新日期:2015-06-01 00:00:00

  • Structure-activity relationships in the ansamycins. Molecular structure and activity of 3-carbomethoxy rifamycin S.

    abstract::The X-ray and NMR structural study of 3-carbomethoxy rifamycin S5 was undertaken in order to determine whether its low antimicrobial activity was related to a conformation of the molecule which was unfavorable for interaction with bacterial DNA-dependent RNA polymerase. However, the molecule assumes a conformation sim...

    journal_title:Molecular pharmacology

    pub_type: 杂志文章

    doi:

    authors: Brufani M,Cellai L,Cerrini S,Fedeli W,Segre A,Vaciago A

    更新日期:1982-03-01 00:00:00

  • Mechanisms underlying nonsteroidal anti-inflammatory drug-induced p27(Kip1) expression.

    abstract::We demonstrated previously that nonsteroidal anti-inflammatory drugs (NSAIDs) increased p27(Kip1) by inhibiting protein degradation to suppress the proliferation of human lung cancer cells. In this study, we elucidate the molecular mechanism by which NSAIDs modulate p27(Kip1) proteolysis. Immunoblotting and in vitro u...

    journal_title:Molecular pharmacology

    pub_type: 杂志文章

    doi:10.1124/mol.62.6.1515

    authors: Huang YC,Chuang LY,Hung WC

    更新日期:2002-12-01 00:00:00

  • Attenuation of agonist-induced desensitization of the rat substance P receptor by microinjection of inositol pentakis-and hexakisphosphates in Xenopus laevis oocytes.

    abstract::Recently, inositol hexakisphosphate (phytic acid) was shown to bind to photoreceptor arrestin and block its interaction with rhodopsin. Such an interaction might predict that inositol polyphosphates could alter G protein-coupled receptor desensitization. To investigate the possible roles of higher inositol polyphospha...

    journal_title:Molecular pharmacology

    pub_type: 杂志文章

    doi:

    authors: Sasakawa N,Ferguson JE,Sharif M,Hanley MR

    更新日期:1994-08-01 00:00:00

  • Bifunctional DNA alkylator 1,3-bis(2-chloroethyl)-1-nitrosourea activates the ATR-Chk1 pathway independently of the mismatch repair pathway.

    abstract::The presence of DNA damage initiates signaling through the ataxia-telangiectasia mutated kinase (ATM) and the ATM- and the Rad3-related kinase (ATR), which phosphorylate, thus activating, the checkpoint kinases (Chk) 1 and 2, which leads to cell cycle arrest. The bifunctional DNA alkylator 1,3-bis(2-chloroethyl)-1-nit...

    journal_title:Molecular pharmacology

    pub_type: 杂志文章

    doi:10.1124/mol.108.053124

    authors: Cui B,Johnson SP,Bullock N,Ali-Osman F,Bigner DD,Friedman HS

    更新日期:2009-06-01 00:00:00

  • AMP Kinase Activation Alters Oxidant-Induced Stress Granule Assembly by Modulating Cell Signaling and Microtubule Organization.

    abstract::Eukaryotic cells assemble stress granules (SGs) when translation initiation is inhibited. Different cell signaling pathways regulate SG production. Particularly relevant to this process is 5'-AMP-activated protein kinase (AMPK), which functions as a stress sensor and is transiently activated by adverse physiologic con...

    journal_title:Molecular pharmacology

    pub_type: 杂志文章

    doi:10.1124/mol.116.105494

    authors: Mahboubi H,Koromilas AE,Stochaj U

    更新日期:2016-10-01 00:00:00

  • A subtype of nicotinic cholinergic receptor in rat brain is composed of alpha 4 and beta 2 subunits and is up-regulated by chronic nicotine treatment.

    abstract::The subunit composition and pharmacological regulation of rat neuronal nicotinic cholinergic receptors were assessed. Specific immunoprecipitation was determined in solubilized rat brain homogenates using [3H]cytisine, a high affinity agonist at nicotinic receptors, in conjunction with polyclonal antisera generated ag...

    journal_title:Molecular pharmacology

    pub_type: 杂志文章

    doi:

    authors: Flores CM,Rogers SW,Pabreza LA,Wolfe BB,Kellar KJ

    更新日期:1992-01-01 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

  • Novel brain-specific 5-HT4 receptor splice variants show marked constitutive activity: role of the C-terminal intracellular domain.

    abstract::We have cloned new 5-Hydroxytryptamine 4 (5-HT4) receptor splice variants from mouse (m5-HT4(e)R and m5-HT4(f)R), rat (r5-HT4(e)R), and human brain tissue (h5-HT4(e)R) which differ, as do the previously described 5-HT4 receptor variants, in the length and composition of their intracellular C termini after the common s...

    journal_title:Molecular pharmacology

    pub_type: 杂志文章

    doi:

    authors: Claeysen S,Sebben M,Becamel C,Bockaert J,Dumuis A

    更新日期:1999-05-01 00:00:00

  • Structure of Cytochrome P450 2C9*2 in Complex with Losartan: Insights into the Effect of Genetic Polymorphism.

    abstract::The human CYP2C9 plays a crucial role in the metabolic clearance of a wide range of clinical therapeutics. The *2 allele is a prevalent genetic variation in CYP2C9 that is found in various populations. A marked reduction of catalytic activity toward many important drug substrates has been demonstrated by CYP2C9*2, whi...

    journal_title:Molecular pharmacology

    pub_type: 杂志文章

    doi:10.1124/molpharm.120.000042

    authors: Parikh SJ,Evans CM,Obi JO,Zhang Q,Maekawa K,Glass KC,Shah MB

    更新日期:2020-11-01 00:00:00

  • Charged amino acids in the transmembrane domains are involved in the determination of the substrate specificity of rat Mrp2.

    abstract::Multidrug resistance-associated protein 2 (MRP2) transports glutathione conjugates, glucuronide conjugates, and sulfated conjugates of bile acids. In the present study, we examined the role of charged amino acids in the transmembrane domains of rat Mrp2, conserved among MRP families, using the isolated membrane vesicl...

    journal_title:Molecular pharmacology

    pub_type: 杂志文章

    doi:10.1124/mol.59.5.1077

    authors: Ito K,Suzuki H,Sugiyama Y

    更新日期:2001-05-01 00:00:00

  • Malaria parasites are rapidly killed by dantrolene derivatives specific for the plasmodial surface anion channel.

    abstract::Dantrolene was recently identified as a novel inhibitor of the plasmodial surface anion channel (PSAC), an unusual ion channel on Plasmodium falciparum-infected human red blood cells. Because dantrolene is used clinically, has a high therapeutic index, and has desirable chemical synthetic properties, it may be a lead ...

    journal_title:Molecular pharmacology

    pub_type: 杂志文章

    doi:10.1124/mol.104.010553

    authors: Kang M,Lisk G,Hollingworth S,Baylor SM,Desai SA

    更新日期:2005-07-01 00:00:00

  • Involvement of tissue plasminogen activator-plasmin system in depolarization-evoked dopamine release in the nucleus accumbens of mice.

    abstract::Tissue plasminogen activator (tPA), a serine protease, catalyzes the conversion of plasminogen to plasmin. In the present study, we investigated the role of the tPA-plasmin system in depolarization-evoked dopamine (DA) and acetylcholine (ACh) release in the nucleus accumbens (NAc) and hippocampus, respectively, of mic...

    journal_title:Molecular pharmacology

    pub_type: 杂志文章

    doi:10.1124/mol.106.022467

    authors: Ito M,Nagai T,Kamei H,Nakamichi N,Nabeshima T,Takuma K,Yamada K

    更新日期:2006-11-01 00:00:00

  • cAMP Signaling Compartmentation: Adenylyl Cyclases as Anchors of Dynamic Signaling Complexes.

    abstract::It is widely accepted that cAMP signaling is compartmentalized within cells. However, our knowledge of how receptors, cAMP signaling enzymes, effectors, and other key proteins form specific signaling complexes to regulate specific cell responses is limited. The multicomponent nature of these systems and the spatiotemp...

    journal_title:Molecular pharmacology

    pub_type: 杂志文章,评审

    doi:10.1124/mol.117.110825

    authors: Johnstone TB,Agarwal SR,Harvey RD,Ostrom RS

    更新日期:2018-04-01 00:00:00

  • Regulation of the stability of P-glycoprotein by ubiquitination.

    abstract::Ubiquitination plays a crucial role in regulating protein turnover. Here we show that ubiquitination regulates the stability of the MDR1 gene product, P-glycoprotein, thereby affecting the functions of this membrane transporter that mediates multidrug resistance. We found that P-glycoprotein was constitutively ubiquit...

    journal_title:Molecular pharmacology

    pub_type: 杂志文章

    doi:10.1124/mol.104.001966

    authors: Zhang Z,Wu JY,Hait WN,Yang JM

    更新日期:2004-09-01 00:00:00

  • Density gradient profiles of A1 adenosine receptors labeled by agonist and antagonist radioligands before and after detergent solubilization.

    abstract::A1 adenosine receptors in bovine cerebral cortex have been solubilized and subjected to sedimentation analysis using sucrose density gradient centrifugation. Because the receptors bound both agonists and antagonists with high affinity after solubilization, receptors labeled with an agonist or an antagonist radioligand...

    journal_title:Molecular pharmacology

    pub_type: 杂志文章

    doi:

    authors: Leung E,Green RD

    更新日期:1989-09-01 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

  • Prostaglandin E2 inhibits the phospholipase D pathway stimulated by formyl-methionyl-leucyl-phenylalanine in human neutrophils. Involvement of EP2 receptors and phosphatidylinositol 3-kinase gamma.

    abstract::Prostaglandin E(2) (PGE(2)), originally discovered as a pro-inflammatory mediator, also inhibits several chemoattractant-elicited neutrophil functions, including adhesion, secretion of cytotoxic enzymes, production of superoxide anions, and chemotaxis. In this study, we have examined the effects of PGE(2) and prostagl...

    journal_title:Molecular pharmacology

    pub_type: 杂志文章

    doi:10.1124/mol.66.2.293

    authors: Burelout C,Thibault N,Levasseur S,Simard S,Naccache PH,Bourgoin SG

    更新日期:2004-08-01 00:00:00

  • High-throughput screening reveals a small-molecule inhibitor of the renal outer medullary potassium channel and Kir7.1.

    abstract::The renal outer medullary potassium channel (ROMK) is expressed in the kidney tubule and critically regulates sodium and potassium balance. The physiological functions of other inward rectifying K(+) (Kir) channels expressed in the nephron, such as Kir7.1, are less well understood in part due to the lack of selective ...

    journal_title:Molecular pharmacology

    pub_type: 杂志文章

    doi:10.1124/mol.109.059840

    authors: Lewis LM,Bhave G,Chauder BA,Banerjee S,Lornsen KA,Redha R,Fallen K,Lindsley CW,Weaver CD,Denton JS

    更新日期:2009-11-01 00:00:00

  • Structure of the saxitoxin binding site at sodium channels in nerve membranes. Exchange of tritium from bound toxin molecules.

    abstract::The exchange of tritium into water from saxitoxin molecules that were radiolabeled at the C-11 methylene position was measured at 37 degrees in solution and in suspensions of brain membranes. High concentrations of membrane receptors were used to assure that more than 80% of the total saxitoxin (STX) present was speci...

    journal_title:Molecular pharmacology

    pub_type: 杂志文章

    doi:

    authors: Strichartz G

    更新日期:1982-03-01 00:00:00

  • Closure of gap junction channels by arylaminobenzoates.

    abstract::We determined the effect of flufenamic acid (FFA) and related derivatives on gap junction channel currents, applying the dual whole-cell patch-clamp technique to pairs of N2A neuroblastoma cells transfected with various connexins. FFA reduced gap junction channel currents in a reversible and concentration-dependent ma...

    journal_title:Molecular pharmacology

    pub_type: 杂志文章

    doi:10.1124/mol.63.6.1389

    authors: Srinivas M,Spray DC

    更新日期:2003-06-01 00:00:00

  • Direct evidence for the existence and functional role of hyperreactive sulfhydryls on the ryanodine receptor-triadin complex selectively labeled by the coumarin maleimide 7-diethylamino-3-(4'-maleimidylphenyl)-4-methylcoumarin.

    abstract::The fluorogenic sulfhydryl probe 7-diethylamino-3-(4'-maleimidylphenyl)-4-methylcoumarin (CPM) (1-50 nM) is used to characterize the functional role and location of highly reactive thiol groups on the ryanodine-sensitive Ca2+ release channel complex [i.e., ryanodine receptors (RyRs)] of skeletal and cardiac junctional...

    journal_title:Molecular pharmacology

    pub_type: 杂志文章

    doi:

    authors: Liu G,Abramson JJ,Zable AC,Pessah IN

    更新日期:1994-02-01 00:00:00

  • Protection against toxic redox cycles between benzo(a)pyrene-3,6-quinone and its quinol by 3-methylcholanthrene-inducible formation of the quinol mono- and diglucuronide.

    abstract::Cytotoxic effects of quinones are thought to be mediated by redox cycles between quinones and quinols whereby reactive oxygen species are generated. The role of glucuronidation in preventing these toxic redox cycles was investigated by using benzo(a)pyrene-3,6-quinone and isolated rat hepatocytes or Reuber hepatoma ce...

    journal_title:Molecular pharmacology

    pub_type: 杂志文章

    doi:

    authors: Lilienblum W,Bock-Hennig BS,Bock KW

    更新日期:1985-04-01 00:00:00

  • Activation of the mitogen activated protein kinase extracellular signal-regulated kinase 1 and 2 by the nitric oxide-cGMP-cGMP-dependent protein kinase axis regulates the expression of matrix metalloproteinase 13 in vascular endothelial cells.

    abstract::Matrix metalloproteinases (MMPs) are synthesized in response to diverse stimuli, including cytokines, growth factors, hormones, and oxidative stress. Here we show that the nitric oxide (NO) donor 2-(N,N-diethylamino)-diazenolate-2-oxide (DEA-NO) and NO from murine macrophages transcriptionally regulate MMP-13 expressi...

    journal_title:Molecular pharmacology

    pub_type: 杂志文章

    doi:10.1124/mol.62.4.927

    authors: Zaragoza C,Soria E,López E,Browning D,Balbín M,López-Otín C,Lamas S

    更新日期:2002-10-01 00:00:00