Gordon D

References (13)

Title : Identification of Reversible Small Molecule Inhibitors of Endothelial Lipase (EL) That Demonstrate HDL-C Increase In Vivo - Tora_2020_J.Med.Chem_63_1660
Author(s) : Tora G , Kim SH , Pi Z , Johnson JA , Jiang J , Phillips M , Lloyd J , Abell LM , Lu H , Locke G , Adam LP , Taylor DS , Yin X , Behnia K , Zhao L , Yang R , Basso M , Caporuscio C , Chen AY , Liu E , Kirshgessner T , Onorato JM , Ryan C , Traeger SC , Gordon D , Wexler RR , Finlay HJ
Ref : Journal of Medicinal Chemistry , 63 :1660 , 2020
Abstract : Endothelial lipase (EL) hydrolyzes phospholipids in high-density lipoprotein (HDL) resulting in reduction in plasma HDL levels. Studies with murine transgenic, KO, or loss-of-function variants strongly suggest that inhibition of EL will lead to sustained plasma high-density lipoprotein cholesterol (HDL-C) increase and, potentially, a reduced cardiovascular disease (CVD) risk. Herein, we describe the discovery of a series of oxadiazole ketones, which upon optimization, led to the identification of compound 12. Compound 12 was evaluated in a mouse pharmacodynamics (PD) model and demonstrated a 56% increase in plasma HDL-C. In a mouse reverse cholesterol transport study, compound 12 stimulated cholesterol efflux by 53% demonstrating HDL-C functionality.
ESTHER : Tora_2020_J.Med.Chem_63_1660
PubMedSearch : Tora_2020_J.Med.Chem_63_1660
PubMedID: 31990537

Title : Identification of substituted benzothiazole sulfones as potent and selective inhibitors of endothelial lipase - Kim_2019_Bioorg.Med.Chem.Lett_29_1918
Author(s) : Kim SH , Johnson JA , Jiang J , Parkhurst B , Phillips M , Pi Z , Qiao JX , Tora G , Ye Chen A , Liu E , Yin X , Yang R , Zhao L , Taylor DS , Basso M , Behnia K , Onorato J , Chen XQ , Abell LM , Lu H , Locke G , Caporuscio C , Adam LP , Gordon D , Wexler RR , Finlay HJ
Ref : Bioorganic & Medicinal Chemistry Lett , 29 :1918 , 2019
Abstract : A low level of high density lipoprotein (HDL) is an independent risk factor for cardiovascular disease. HDL reduces inflammation and plays a central role in reverse cholesterol transport, where cholesterol is removed from peripheral tissues and atherosclerotic plaque. One approach to increase plasma HDL is through inhibition of endothelial lipase (EL). EL hydrolyzes phospholipids in HDL resulting in reduction of plasma HDL. A series of benzothiazole sulfone amides was optimized for EL inhibition potency, lipase selectivity and improved pharmacokinetic profile leading to the identification of Compound 32. Compound 32 was evaluated in a mouse pharmacodynamic model and found to show no effect on HDL cholesterol level despite achieving targeted plasma exposure (Ctrough>15 fold over mouse plasma EL IC50 over 4days).
ESTHER : Kim_2019_Bioorg.Med.Chem.Lett_29_1918
PubMedSearch : Kim_2019_Bioorg.Med.Chem.Lett_29_1918
PubMedID: 31176700
Gene_locus related to this paper: human-LIPG

Title : Discovery and synthesis of tetrahydropyrimidinedione-4-carboxamides as endothelial lipase inhibitors - Hu_2018_Bioorg.Med.Chem.Lett_28_3721
Author(s) : Hu CH , Wang TC , Qiao JX , Haque L , Chen AYA , Taylor DS , Ying X , Onorato JM , Galella M , Shen H , Huang CS , Toussaint N , Li YX , Abell L , Adam LP , Gordon D , Wexler RR , Finlay HJ
Ref : Bioorganic & Medicinal Chemistry Lett , 28 :3721 , 2018
Abstract : Endothelial lipase (EL) inhibitors have been shown to elevate HDL-C levels in pre-clinical murine models and have potential benefit in prevention and treatment of cardiovascular diseases. Modification of the 1-ethyl-3-hydroxy-1,5-dihydro-2H-pyrrol-2-one (DHP) lead, 1, led to the discovery of a series of potent tetrahydropyrimidinedione (THP) EL inhibitors. Synthesis and SAR studies including modification of the amide group, together with changes on the pyrimidinone core led to a series of arylcycloalkyl, indanyl, and tetralinyl substituted 5-amino or 5-hydroxypyrimidinedione-4-carboxamides. Several compounds were advanced to PK evaluation. Among them, compound 4a was one of the most potent with measurable EL(HDL) hSerum potency and compound 3g demonstrated the best overall pharmacokinetic parameters.
ESTHER : Hu_2018_Bioorg.Med.Chem.Lett_28_3721
PubMedSearch : Hu_2018_Bioorg.Med.Chem.Lett_28_3721
PubMedID: 30348490

Title : Sulfonylated Benzothiazoles as Inhibitors of Endothelial Lipase - Johnson_2018_ACS.Med.Chem.Lett_9_1263
Author(s) : Johnson JA , Tora G , Pi Z , Phillips M , Yin X , Yang R , Zhao L , Chen AY , Taylor DS , Basso M , Rose A , Behnia K , Onorato J , Chen XQ , Abell LM , Lu H , Locke G , Caporuscio C , Galella M , Adam LP , Gordon D , Wexler RR , Finlay HJ
Ref : ACS Med Chem Lett , 9 :1263 , 2018
Abstract : Endothelial lipase (EL) selectively metabolizes high density lipoprotein (HDL) particles. Inhibition of EL has been shown to increase HDL concentration in preclinical animal models and was targeted as a potential treatment of atherosclerosis. We describe the introduction of an alpha-sulfone moiety to a benzothiazole series of EL inhibitors resulting in increased potency versus EL. Optimization for selectivity versus hepatic lipase and pharmacokinetic properties resulted in the discovery of 24, which showed good in vitro potency and bioavailability but, unexpectedly, did not increase HDL in the mouse pharmacodynamic model at the target plasma exposure.
ESTHER : Johnson_2018_ACS.Med.Chem.Lett_9_1263
PubMedSearch : Johnson_2018_ACS.Med.Chem.Lett_9_1263
PubMedID: 30613337
Gene_locus related to this paper: human-LIPG

Title : The zebrafish reference genome sequence and its relationship to the human genome - Howe_2013_Nature_496_498
Author(s) : Howe K , Clark MD , Torroja CF , Torrance J , Berthelot C , Muffato M , Collins JE , Humphray S , McLaren K , Matthews L , Mclaren S , Sealy I , Caccamo M , Churcher C , Scott C , Barrett JC , Koch R , Rauch GJ , White S , Chow W , Kilian B , Quintais LT , Guerra-Assuncao JA , Zhou Y , Gu Y , Yen J , Vogel JH , Eyre T , Redmond S , Banerjee R , Chi J , Fu B , Langley E , Maguire SF , Laird GK , Lloyd D , Kenyon E , Donaldson S , Sehra H , Almeida-King J , Loveland J , Trevanion S , Jones M , Quail M , Willey D , Hunt A , Burton J , Sims S , McLay K , Plumb B , Davis J , Clee C , Oliver K , Clark R , Riddle C , Elliot D , Threadgold G , Harden G , Ware D , Begum S , Mortimore B , Kerry G , Heath P , Phillimore B , Tracey A , Corby N , Dunn M , Johnson C , Wood J , Clark S , Pelan S , Griffiths G , Smith M , Glithero R , Howden P , Barker N , Lloyd C , Stevens C , Harley J , Holt K , Panagiotidis G , Lovell J , Beasley H , Henderson C , Gordon D , Auger K , Wright D , Collins J , Raisen C , Dyer L , Leung K , Robertson L , Ambridge K , Leongamornlert D , McGuire S , Gilderthorp R , Griffiths C , Manthravadi D , Nichol S , Barker G , Whitehead S , Kay M , Brown J , Murnane C , Gray E , Humphries M , Sycamore N , Barker D , Saunders D , Wallis J , Babbage A , Hammond S , Mashreghi-Mohammadi M , Barr L , Martin S , Wray P , Ellington A , Matthews N , Ellwood M , Woodmansey R , Clark G , Cooper J , Tromans A , Grafham D , Skuce C , Pandian R , Andrews R , Harrison E , Kimberley A , Garnett J , Fosker N , Hall R , Garner P , Kelly D , Bird C , Palmer S , Gehring I , Berger A , Dooley CM , Ersan-Urun Z , Eser C , Geiger H , Geisler M , Karotki L , Kirn A , Konantz J , Konantz M , Oberlander M , Rudolph-Geiger S , Teucke M , Lanz C , Raddatz G , Osoegawa K , Zhu B , Rapp A , Widaa S , Langford C , Yang F , Schuster SC , Carter NP , Harrow J , Ning Z , Herrero J , Searle SM , Enright A , Geisler R , Plasterk RH , Lee C , Westerfield M , de Jong PJ , Zon LI , Postlethwait JH , Nusslein-Volhard C , Hubbard TJ , Roest Crollius H , Rogers J , Stemple DL
Ref : Nature , 496 :498 , 2013
Abstract : Zebrafish have become a popular organism for the study of vertebrate gene function. The virtually transparent embryos of this species, and the ability to accelerate genetic studies by gene knockdown or overexpression, have led to the widespread use of zebrafish in the detailed investigation of vertebrate gene function and increasingly, the study of human genetic disease. However, for effective modelling of human genetic disease it is important to understand the extent to which zebrafish genes and gene structures are related to orthologous human genes. To examine this, we generated a high-quality sequence assembly of the zebrafish genome, made up of an overlapping set of completely sequenced large-insert clones that were ordered and oriented using a high-resolution high-density meiotic map. Detailed automatic and manual annotation provides evidence of more than 26,000 protein-coding genes, the largest gene set of any vertebrate so far sequenced. Comparison to the human reference genome shows that approximately 70% of human genes have at least one obvious zebrafish orthologue. In addition, the high quality of this genome assembly provides a clearer understanding of key genomic features such as a unique repeat content, a scarcity of pseudogenes, an enrichment of zebrafish-specific genes on chromosome 4 and chromosomal regions that influence sex determination.
ESTHER : Howe_2013_Nature_496_498
PubMedSearch : Howe_2013_Nature_496_498
PubMedID: 23594743
Gene_locus related to this paper: danre-1neur , danre-ABHD10b , danre-a9jrf7 , danre-d2x2g3 , danre-e7ezq9 , danre-e7ff77 , danre-ndr3 , danre-nlgn4a , danre-q1mti5 , danre-q6nyz4 , danre-q6p2u2 , danre-q7t359 , danre-q08c93 , danre-A2BGU9 , danre-f1q676 , danre-e7f0z8 , danre-e7ez27 , danre-e7f2w1 , danre-f1qid7 , danre-a0a0g2kru2 , danre-f1qla7 , danre-a9jr90 , danre-e7f070 , danre-f172a , danre-e7fb35 , danre-a7mbu9 , danre-f1qtr2

Title : Autonomic remodeling in the left atrium and pulmonary veins in heart failure: creation of a dynamic substrate for atrial fibrillation - Ng_2011_Circ.Arrhythm.Electrophysiol_4_388
Author(s) : Ng J , Villuendas R , Cokic I , Schliamser JE , Gordon D , Koduri H , Benefield B , Simon J , Murthy SN , Lomasney JW , Wasserstrom JA , Goldberger JJ , Aistrup GL , Arora R
Ref : Circ Arrhythm Electrophysiol , 4 :388 , 2011
Abstract : BACKGROUND: Atrial fibrillation (AF) is commonly associated with congestive heart failure (CHF). The autonomic nervous system is involved in the pathogenesis of both AF and CHF. We examined the role of autonomic remodeling in contributing to AF substrate in CHF. METHODS AND RESULTS: Electrophysiological mapping was performed in the pulmonary veins and left atrium in 38 rapid ventricular-paced dogs (CHF group) and 39 control dogs under the following conditions: vagal stimulation, isoproterenol infusion, beta-adrenergic blockade, acetylcholinesterase (AChE) inhibition (physostigmine), parasympathetic blockade, and double autonomic blockade. Explanted atria were examined for nerve density/distribution, muscarinic receptor and beta-adrenergic receptor densities, and AChE activity. In CHF dogs, there was an increase in nerve bundle size, parasympathetic fibers/bundle, and density of sympathetic fibrils and cardiac ganglia, all preferentially in the posterior left atrium/pulmonary veins. Sympathetic hyperinnervation was accompanied by increases in beta(1)-adrenergic receptor R density and in sympathetic effect on effective refractory periods and activation direction. beta-Adrenergic blockade slowed AF dominant frequency. Parasympathetic remodeling was more complex, resulting in increased AChE activity, unchanged muscarinic receptor density, unchanged parasympathetic effect on activation direction and decreased effect of vagal stimulation on effective refractory period (restored by AChE inhibition). Parasympathetic blockade markedly decreased AF duration. CONCLUSIONS: In this heart failure model, autonomic and electrophysiological remodeling occurs, involving the posterior left atrium and pulmonary veins. Despite synaptic compensation, parasympathetic hyperinnervation contributes significantly to AF maintenance. Parasympathetic and/or sympathetic signaling may be possible therapeutic targets for AF in CHF.
ESTHER : Ng_2011_Circ.Arrhythm.Electrophysiol_4_388
PubMedSearch : Ng_2011_Circ.Arrhythm.Electrophysiol_4_388
PubMedID: 21421805

Title : Quantitative analysis of parasympathetic innervation of the porcine heart - Ulphani_2010_Heart.Rhythm_7_1113
Author(s) : Ulphani JS , Cain JH , Inderyas F , Gordon D , Gikas PV , Shade G , Mayor D , Arora R , Kadish AH , Goldberger JJ
Ref : Heart Rhythm , 7 :1113 , 2010
Abstract : BACKGROUND: Parasympathetic control of the heart is an important component in the regulation of normal cardiac function. However, the anatomic course of parasympathetic innervation of the heart is unclear. OBJECTIVE: The purpose of this study was to apply a gross parasympathetic nerve stain technique to reveal the details of the morphology of the cardiac parasympathetic nervous system. METHODS: Ten whole pig hearts were stained using a histochemical method. Immediately after sacrifice, hearts were placed in a buffered solution containing acetylthiocholine, which precipitates with acetylcholinesterase, allowing identification of cholinergic nerves. The epicardial and endocardial surfaces of the atria and ventricles were examined for nerve thickness and density. RESULTS: In both atria, nerve density was significantly greater on the endocardium, but nerve thickness was significantly greater on the epicardium. The right atrium (RA) was more densely innervated than the left atrium (LA) on the endocardium, whereas the LA was more densely innervated than the RA on the epicardium. In the ventricles, numerous thick cholinergic nerves were clearly identifiable across the epicardium, generally running parallel to the left anterior descending artery. The endocardial surfaces of the ventricles revealed a dense network of fine parasympathetic nerve fibers. As in the atria, nerve density was greater on the ventricular endocardium, but nerve thickness was greater on the epicardium. The right ventricle (RV) was more densely innervated than the left ventricle (LV), whereas the LV endocardium was more densely innervated than the RV endocardium. CONCLUSION: The epicardial and endocardial surfaces of the atria and ventricles are richly innervated by parasympathetic nerves. The density of parasympathetic innervation is heterogeneous across both the epicardial and endocardial surfaces of the heart.
ESTHER : Ulphani_2010_Heart.Rhythm_7_1113
PubMedSearch : Ulphani_2010_Heart.Rhythm_7_1113
PubMedID: 20381645

Title : The ligament of Marshall as a parasympathetic conduit - Ulphani_2007_Am.J.Physiol.Heart.Circ.Physiol_293_H1629
Author(s) : Ulphani JS , Arora R , Cain JH , Villuendas R , Shen S , Gordon D , Inderyas F , Harvey LA , Morris A , Goldberger JJ , Kadish AH
Ref : American Journal of Physiology Heart Circ Physiol , 293 :H1629 , 2007
Abstract : The objective of the study was to investigate the morphology, distribution, and electrophysiological profile of the autonomic fibers that innervate the ligament of Marshall (LOM). Gross anatomical dissections were performed in 10 dogs. Sections of the left vagus nerve, left stellate ganglion, and the LOM were immunostained to identify adrenergic and cholinergic nerves. Hearts were also stained for acetylcholinesterase to identify epicardial cholinergic nerves. In vivo electrophysiological studies were performed in another 10 dogs before and after LOM ablation. The anatomical examination revealed that the LOM is innervated by a branch of the left vagus. Immunohistochemistry confirmed that these nerve bundles are predominantly cholinergic (cholinergic-to-adrenergic ratio of 12.6 +/- 3.9:1). Cholinergic nerves originating in the LOM were found to innervate surrounding left atrial structures, including the pulmonary veins, left atrial appendage, coronary sinus, and posterior left atrial fat pad. Ablation of the LOM significantly attenuated effective refractory period shortening at distant sites, such as pulmonary veins and left atrial appendage, in response to vagal stimulation (vagal-induced ERP decrease in the left atrium: baseline vs. postablation = 17 vs. 4%; P = 0.0056). In conclusion, the LOM contains a predominance of cholinergic nerve fibers. Cholinergic fibers arising from the LOM innervate surrounding structures and contribute to the electrophysiological profile of the left atrium. These findings may provide a basis for the role of the LOM in the genesis and maintenance of atrial fibrillation.
ESTHER : Ulphani_2007_Am.J.Physiol.Heart.Circ.Physiol_293_H1629
PubMedSearch : Ulphani_2007_Am.J.Physiol.Heart.Circ.Physiol_293_H1629
PubMedID: 17545480

Title : d-Conopeptide EVIA isolated from Conus ermineus is a new pharmacological tool for discriminating sodium channel subtypes -
Author(s) : Barbier J , Lamthanh H , Gall FL , Favreau P , Benoit E , Chen H , Gilles N , Ilan N , Heinemann SH , Gordon D , Menez A , Molgo J
Ref : Journal de Physiologie (Paris) , 99 :247 , 2006

Title : The DNA sequence and biology of human chromosome 19 - Grimwood_2004_Nature_428_529
Author(s) : Grimwood J , Gordon LA , Olsen A , Terry A , Schmutz J , Lamerdin J , Hellsten U , Goodstein D , Couronne O , Tran-Gyamfi M , Aerts A , Altherr M , Ashworth L , Bajorek E , Black S , Branscomb E , Caenepeel S , Carrano A , Caoile C , Chan YM , Christensen M , Cleland CA , Copeland A , Dalin E , Dehal P , Denys M , Detter JC , Escobar J , Flowers D , Fotopulos D , Garcia C , Georgescu AM , Glavina T , Gomez M , Gonzales E , Groza M , Hammon N , Hawkins T , Haydu L , Ho I , Huang W , Israni S , Jett J , Kadner K , Kimball H , Kobayashi A , Larionov V , Leem SH , Lopez F , Lou Y , Lowry S , Malfatti S , Martinez D , McCready P , Medina C , Morgan J , Nelson K , Nolan M , Ovcharenko I , Pitluck S , Pollard M , Popkie AP , Predki P , Quan G , Ramirez L , Rash S , Retterer J , Rodriguez A , Rogers S , Salamov A , Salazar A , She X , Smith D , Slezak T , Solovyev V , Thayer N , Tice H , Tsai M , Ustaszewska A , Vo N , Wagner M , Wheeler J , Wu K , Xie G , Yang J , Dubchak I , Furey TS , DeJong P , Dickson M , Gordon D , Eichler EE , Pennacchio LA , Richardson P , Stubbs L , Rokhsar DS , Myers RM , Rubin EM , Lucas SM
Ref : Nature , 428 :529 , 2004
Abstract : Chromosome 19 has the highest gene density of all human chromosomes, more than double the genome-wide average. The large clustered gene families, corresponding high G + C content, CpG islands and density of repetitive DNA indicate a chromosome rich in biological and evolutionary significance. Here we describe 55.8 million base pairs of highly accurate finished sequence representing 99.9% of the euchromatin portion of the chromosome. Manual curation of gene loci reveals 1,461 protein-coding genes and 321 pseudogenes. Among these are genes directly implicated in mendelian disorders, including familial hypercholesterolaemia and insulin-resistant diabetes. Nearly one-quarter of these genes belong to tandemly arranged families, encompassing more than 25% of the chromosome. Comparative analyses show a fascinating picture of conservation and divergence, revealing large blocks of gene orthology with rodents, scattered regions with more recent gene family expansions and deletions, and segments of coding and non-coding conservation with the distant fish species Takifugu.
ESTHER : Grimwood_2004_Nature_428_529
PubMedSearch : Grimwood_2004_Nature_428_529
PubMedID: 15057824

Title : The genome of the natural genetic engineer Agrobacterium tumefaciens C58 - Wood_2001_Science_294_2317
Author(s) : Wood DW , Setubal JC , Kaul R , Monks DE , Kitajima JP , Okura VK , Zhou Y , Chen L , Wood GE , Almeida NF, Jr. , Woo L , Chen Y , Paulsen IT , Eisen JA , Karp PD , Bovee D, Sr. , Chapman P , Clendenning J , Deatherage G , Gillet W , Grant C , Kutyavin T , Levy R , Li MJ , McClelland E , Palmieri A , Raymond C , Rouse G , Saenphimmachak C , Wu Z , Romero P , Gordon D , Zhang S , Yoo H , Tao Y , Biddle P , Jung M , Krespan W , Perry M , Gordon-Kamm B , Liao L , Kim S , Hendrick C , Zhao ZY , Dolan M , Chumley F , Tingey SV , Tomb JF , Gordon MP , Olson MV , Nester EW
Ref : Science , 294 :2317 , 2001
Abstract : The 5.67-megabase genome of the plant pathogen Agrobacterium tumefaciens C58 consists of a circular chromosome, a linear chromosome, and two plasmids. Extensive orthology and nucleotide colinearity between the genomes of A. tumefaciens and the plant symbiont Sinorhizobium meliloti suggest a recent evolutionary divergence. Their similarities include metabolic, transport, and regulatory systems that promote survival in the highly competitive rhizosphere; differences are apparent in their genome structure and virulence gene complement. Availability of the A. tumefaciens sequence will facilitate investigations into the molecular basis of pathogenesis and the evolutionary divergence of pathogenic and symbiotic lifestyles.
ESTHER : Wood_2001_Science_294_2317
PubMedSearch : Wood_2001_Science_294_2317
PubMedID: 11743193
Gene_locus related to this paper: agrt5-a9cf94 , agrt5-a9cfa9 , agrt5-a9cfs8 , agrt5-a9cfu7 , agrt5-a9cie7 , agrt5-a9cj11 , agrt5-a9cjp2 , agrt5-a9cki2 , agrt5-a9ckr2 , agrt5-a9ckt2 , agrt5-a9cle4 , agrt5-a9clq8 , agrt5-a9clq9 , agrt5-q7cx24 , agrt5-q7d1j0 , agrt5-q7d1j3 , agrt5-q7d3m5 , agrt5-y5261 , agrtu-ACVB , agrtu-ATTS , agrtu-ATU0253 , agrtu-ATU0403 , agrtu-ATU0841 , agrtu-ATU1045 , agrtu-ATU1102 , agrtu-ATU1572 , agrtu-ATU1617 , agrtu-ATU1826 , agrtu-ATU1842 , agrtu-ATU2061 , agrtu-ATU2126 , agrtu-ATU2171 , agrtu-ATU2409 , agrtu-ATU2452 , agrtu-ATU2481 , agrtu-ATU2497 , agrtu-ATU2576 , agrtu-ATU3428 , agrtu-ATU3651 , agrtu-ATU3652 , agrtu-ATU4238 , agrtu-ATU5190 , agrtu-ATU5193 , agrtu-ATU5275 , agrtu-ATU5296 , agrtu-ATU5348 , agrtu-ATU5389 , agrtu-ATU5446 , agrtu-ATU5495 , agrtu-CPO , agrtu-DHAA , agrtu-DLHH , agrtu-EPHA , agrtu-GRST , agrtu-PCA , agrtu-PCAD , agrtu-PHBC , agrtu-PTRB , agrt5-a9cji8

Title : Analysis of nicotinic acetylcholine receptor subunits in the cochlea of the mouse - Drescher_1995_Comp.Biochem.Physiol.C.Pharmacol.Toxicol.Endocrinol_112_267
Author(s) : Drescher DG , Khan KM , Green GE , Morley BJ , Beisel KW , Kaul H , Gordon D , Gupta AK , Drescher MJ , Barretto RL
Ref : Comparative Biochemistry & Physiology C Pharmacol Toxicol Endocrinol , 112 :267 , 1995
Abstract : The present study was designed to catalogue and compare nicotinic receptor subunit messages in the mammalian cochlea. Fourteen nicotinic acetylcholine receptor subunit messages were examined by polymerase chain reaction (PCR) analysis and nucleotide sequencing. Total RNA was extracted from the auditory organs of 14- to 18-day-old CBAJ mice, and mRNA was purified using oligo-dT cellulose. After reverse transcription, resulting cDNA was amplified by PCR with the use of primers specific for the nucleotide sequences representing the following nicotinic receptor subunits: muscle types alpha 1, beta 1, gamma, delta and epsilon and neuronal types alpha 2,3,4,5,6,7 and beta 2,3,4. cDNA from cochlear tissue corresponding to the muscle-type receptor subunit beta 1 and to neuronal-type receptor subunits alpha 2,4,5,6 and beta 2,3 was amplified, whereas cDNA for muscle types alpha 1, gamma, delta and epsilon and neuronal types alpha 3,7 and beta 4 was not. All PCR products were homologous in nucleotide sequence to the corresponding reference cDNAs from which the primers were designed. The current results indicate that nicotinic acetylcholine receptor (nAChR) subunits that are similar or identical to the stated muscle and neuronal types are expressed in the murine cochlea. The presence of messages corresponding to the muscle-type beta 1 and neuronal-type nAChR subunits may be correlated with the atypical cholinergic response of cochlear hair cells to agonists and antagonists.
ESTHER : Drescher_1995_Comp.Biochem.Physiol.C.Pharmacol.Toxicol.Endocrinol_112_267
PubMedSearch : Drescher_1995_Comp.Biochem.Physiol.C.Pharmacol.Toxicol.Endocrinol_112_267
PubMedID: 8838678

Title : Localization of receptor sites for insect-selective toxins on sodium channels by site-directed antibodies - Gordon_1992_Biochemistry_31_7622
Author(s) : Gordon D , Moskowitz H , Eitan M , Warner C , Catterall WA , Zlotkin E
Ref : Biochemistry , 31 :7622 , 1992
Abstract : Site-directed antibodies corresponding to conserved putative extracellular segments of sodium channels, coupled with binding studies of radiolabeled insect-selective scorpion neurotoxins, were employed to clarify the relationship between the toxins' receptor sites and the insect sodium channel. (1) The depressant insect toxin LqhIT2 was shown to possess two noninteracting binding sites in locust neuronal membranes: a high-affinity (KD1 = 0.9 +/- 0.6 nM) and low-capacity (Bmax1 = 0.1 +/- 0.07 pmol/mg) binding site as well as a low-affinity (KD2 = 185 +/- 13 nM) and high-capacity (Bmax2 = 10.0 +/- 0.6 pmol/mg) binding site. (2) The high-affinity site serves as a target for binding competition by the excitatory insect toxin AaIT. (3) The binding of LqhIT2 was significantly inhibited in a dose-dependent manner by each of four site-directed antibodies. The binding inhibition resulted from reduction in the number of binding sites. (4) The antibody-mediated inhibition of [125I]AaIT binding differs from that of LqhIT2: three out of the four antibodies which inhibited LqhIT2 binding only partially affected AaIT binding. Two antibodies, one corresponding to extracellular and one to intracellular segments of the channel, did not affect the binding of either toxin. These data suggest that the receptors to the depressant and excitatory insect toxins (a) comprise an integral part of the insect sodium channel, (b) are formed by segments of external loops in domains I, III, and IV of the sodium channel, and (c) are localized in close proximity but are not identical in spite of the competitive interaction between these toxins.
ESTHER : Gordon_1992_Biochemistry_31_7622
PubMedSearch : Gordon_1992_Biochemistry_31_7622
PubMedID: 1324719