Geoghagen NS

References (4)

Title : Small molecule activation of lecithin cholesterol acyltransferase modulates lipoprotein metabolism in mice and hamsters - Chen_2012_Metabolism_61_470
Author(s) : Chen Z , Wang SP , Krsmanovic ML , Castro-Perez J , Gagen K , Mendoza V , Rosa R , Shah V , He T , Stout SJ , Geoghagen NS , Lee SH , McLaren DG , Wang L , Roddy TP , Plump AS , Hubbard BK , Sinz CJ , Johns DG
Ref : Metabolism , 61 :470 , 2012
Abstract : The objective was to assess whether pharmacological activation of lecithin cholesterol acyltransferase (LCAT) could exert beneficial effects on lipoprotein metabolism. A putative small molecule activator (compound A) was used as a tool compound in in vitro and in vivo studies. Compound A increased LCAT activity in vitro in plasma from mouse, hamster, rhesus monkey, and human. To assess the acute pharmacodynamic effects of compound A, C57Bl/6 mice and hamsters received a single dose (20 mg/kg) of compound A. Both species displayed a significant increase in high-density lipoprotein cholesterol (HDLc) and a significant decrease in non-HDLc and triglycerides acutely after dosing; these changes tracked with ex vivo plasma LCAT activity. To examine compound A's chronic effect on lipoprotein metabolism, hamsters received a daily dosing of vehicle or of 20 or 60 mg/kg of compound A for 2 weeks. At study termination, compound treatment resulted in a significant increase in HDLc, HDL particle size, plasma apolipoprotein A-I level, and plasma cholesteryl ester (CE) to free cholesterol ratio, and a significant reduction in very low-density lipoprotein cholesterol. The increase in plasma CE mirrored the increase in HDL CE. Triglycerides trended toward a dose-dependent decrease in very low-density lipoprotein and HDL, with multiple triglyceride species reaching statistical significance. Gallbladder bile acids content displayed a significant and more than 2-fold increase with the 60 mg/kg treatment. We characterized pharmacological activation of LCAT by a small molecule extensively for the first time, and our findings support the potential of this approach in treating dyslipidemia and atherosclerosis; our analyses also provide mechanistic insight on LCAT's role in lipoprotein metabolism.
ESTHER : Chen_2012_Metabolism_61_470
PubMedSearch : Chen_2012_Metabolism_61_470
PubMedID: 22001333

Title : Poster: Phenotypic interconversion of muscarinic receptor subtypes coupled to phospholipase C by exchanging two amino acids -
Author(s) : Geoghagen NS , Lee NH
Ref : Life Sciences , 60 :1177 , 1997
PubMedID:

Title : Alanine scanning mutagenesis of conserved arginine\/lysine-arginine\/lysine-X-X-arginine\/lysine G protein-activating motifs on m1 muscarinic acetylcholine receptors - Lee_1996_Mol.Pharmacol_50_140
Author(s) : Lee NH , Geoghagen NS , Cheng E , Cline RT , Fraser CM
Ref : Molecular Pharmacology , 50 :140 , 1996
Abstract : Alanine scanning mutagenesis of B-B-X-X-B motifis (where B is a basic residue and X is any nonbasic residue) in m1 muscarinic acetylcholine receptors was performed to determine the relative roles of basic amino acids in receptor coupling. This conserved motif is found in many G protein-coupled receptors and has been implicated in G protein activation. The KKAAR365 motif, located at the carboxyl-terminal third intracellular loop of m1 receptors, was mutated to AAAAA365, thereby generating a triple-substitution mutant devoid of ability to stimulate either phosphoinositide (PI) hydrolysis or cAMP accumulation. In contrast, a triple-alanine substitution of the KRTPR140 motif in the carboxyl-terminal second intracellular loop, yielding mutant AATPA140, had no effect on receptor coupling to the two independent second messenger pathways. Analysis of a series of single- and double-substitution mutants demonstrate that all three basic residues of the KKAAR365 motif participate in efficient m1 receptor coupling. The presence of second and third basic residues in this motif was absolutely critical for full agonist recognition of a high and low affinity state of the receptor. Mutation of either Lys362 or Lys365, but not-Lys361, abolished guanine nucleotide-dependent conversion of agonist affinity states and correlated with an inability of full agonists to fully activate PI hydrolysis. The different combinatorial double-substitution mutants also revealed that Lys365 was necessary but not sufficient, in the context of the KKAAR365 motif, for efficient receptor coupling. This residue cannot facilitate full agonist-stimulated Pl hydrolysis in the absence of both Lys361 and Lys362. In comparison, the critical residue Lys362 was both necessary and sufficient. Substitution of nearby basic residues Lys361 and Lys365 with alanine yielded mutant AKAAA365, which exhibited partial ability to couple PI hydrolysis after full agonist stimulation. Therefore, Lys365 seems to function in a hierarchal (interdependent) manner with nearby basic residues, whereas Lys361 and Lys362 can act independent of surrounding basic residues to facilitate partial m1 receptor coupling after full agonist stimulation. In contrast, all three residues must be present for stimulation of PI hydrolysis by a partial agonist.
ESTHER : Lee_1996_Mol.Pharmacol_50_140
PubMedSearch : Lee_1996_Mol.Pharmacol_50_140
PubMedID: 8700106

Title : Whole-genome random sequencing and assembly of Haemophilus influenzae Rd - Fleischmann_1995_Science_269_496
Author(s) : Fleischmann RD , Adams MD , White O , Clayton RA , Kirkness EF , Kerlavage AR , Bult CJ , Tomb JF , Dougherty BA , Merrick JM , McKenney K , Sutton G , FitzHugh W , Fields C , Gocayne JD , Scott J , Shirley R , Liu LI , Glodek A , Kelley JM , Weidman JF , Phillips CA , Spriggs T , Hedblom E , Cotton MD , Utterback TR , Hanna MC , Nguyen DT , Saudek DM , Brandon RC , FineLD , Fritchman JL , Fuhrmann JL , Geoghagen NS , Gnehm CL , McDonald LA , Keith V , Small KV , Fraser CM , Smith HO , Venter JC
Ref : Science , 269 :496 , 1995
Abstract : An approach for genome analysis based on sequencing and assembly of unselected pieces of DNA from the whole chromosome has been applied to obtain the complete nucleotide sequence (1,830,137 base pairs) of the genome from the bacterium Haemophilus influenzae Rd. This approach eliminates the need for initial mapping efforts and is therefore applicable to the vast array of microbial species for which genome maps are unavailable. The H. influenzae Rd genome sequence (Genome Sequence DataBase accession number L42023) represents the only complete genome sequence from a free-living organism.
ESTHER : Fleischmann_1995_Science_269_496
PubMedSearch : Fleischmann_1995_Science_269_496
PubMedID: 7542800
Gene_locus related to this paper: haein-HI0193 , haein-metx , haein-pldb , haein-sfgh , haein-y1552 , haein-yfbb