Susan M. Fisher
Bristol-Myers Squibb
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Featured researches published by Susan M. Fisher.
Journal of Biological Chemistry | 1997
Patricia M. Rose; Jean S. Lynch; Scott T. Frazier; Susan M. Fisher; Wendy K. Chung; Peter B Battaglino; Zahra Fathi; Rudolph L. Leibel; Prabhavathi Fernandes
Neuropeptide Y is a 36-amino-acid peptide amide with numerous biological activities. These functions are mediated through several pharmacologically distinct receptors. To date five receptor subtypes have been cloned. Here we report the isolation, by low stringency homology cloning from a hypothalamic library, of a cDNA encoding the human homolog of the murine neuropeptide Y receptor subsequently reported (1). Translation of the human Y1-like receptor clone suggested that it encoded a receptor which is truncated in the third extracellular loop. Comparison of the human Y1-like sequence to that of the human Y1 receptor suggested that the truncated receptor could have resulted from a frameshift due to a single nucleotide deletion in the sixth transmembrane domain. Southern blot analysis suggested that the gene is single copy in the human genome. The gene is located on chromosome 5q. To test the hypothesis that allelic variation of nucleic acid length within the sixth transmembrane domain of the Y1-like receptor may exist to produce a functional receptor, genomic DNA from 192 individuals of various ages, ethnic backgrounds, and degrees of obesity were analyzed electrophoretically and by direct sequencing. No variation was detected in any of the subjects, indicating that this receptor subtype may be a transcribed pseudogene in humans.
FEBS Letters | 1995
Patricia M. Rose; Stanley R. Krystek; Pramathesh S. Patel; Eddie C.-K. Liu; Jean S. Lynch; David A. Lach; Susan M. Fisher; Maria L. Webb
The endothelin receptors, ETA and ETB, are G protein‐coupled receptors (GPCR) that show distinctively different binding profiles for the endothelin peptides and other ligands. We recently reported that Tyr129 in the second transmembrane region (TM2) of the ETA receptor was critical for subtype‐specific ligand binding [Krystek, S.R. et al. (1994) J. Biol. Chem. 269, 12383–12386]. Receptor models indicated that aspartic acids located one helical turn above (Asp133) and below (Asp126) Tyr129 in ETA had their side chains directed toward the putative binding cavity. Similarly in ETB, Asp147 and Asp154 are located one turn below and above His150, the residue that corresponds to Tyr129. Asp126 in ETA and Asp147 in ETB corresponds to the highly conserved aspartate present in TM2 of many GPCR that has frequently been shown to be crucial for agonist efficacy. Mutagenesis of Asp126 of the human ETA receptor to alanine resulted in an unaltered affinity for ET‐1, a 160‐fold increase in ET‐3 affinity and a decrease in affinity for the ETA selective naphthalenesulfonamide, BMS‐182874. ET‐1 activation of phospholipase C was abolished. In addition, despite the gain in binding affinity, ET‐3 failed to activate phospholipase C, suggesting that Asp126 is required for signal transduction. Mutagenesis of Asp133 to alanine indicated that it was critical only for the binding of BMS‐182874. In the ETB receptor, mutation of His150 to alanine or tyrosine indicated that it plays a minor role in ETB subtype‐selective ligand binding; mutation of the aspartates in TM2 of ETB did not alter ligand binding. As in the Asp126Ala ETA variant, ET‐1 and ET‐3 failed to increase intracellular levels of inositol phosphates in the Asp147Ala ETB mutant. Taken together, these data support the hypothesis that Asp126 and Asp133 flanking Tyr129 in TM2 of the ETA receptor play a role in defining ETA subtype‐selective ligand binding but Asp147 and Asp154 that flank the His150 in TM2 of the ETB receptor do not. Furthermore, these data indicate that Asp126 in ETA and Asp147 in ETB are important for transmembrane signaling via phospholipase C.
Journal of Cardiovascular Pharmacology | 1993
S. K. Durham; N. L. Goller; Jean S. Lynch; Susan M. Fisher; Patricia M. Rose
Endothelins are a family of potent vasoactive peptides. Full-length cDNA clones to human endothelin receptor B (ETB) mRNA were random prime-labeled with nucleotides conjugated to digoxigenin for in situ hybridization. The labeled cDNA was used to probe frozen sections of rat and rabbit lung. Detection of the digoxigenin-labeled probe was accomplished by an antibody-enzyme conjugate, anti-digoxigenin alkaline phosphatase. The location of the antibody-antigen complex was visualized as an enzyme-linked color reaction. The hybridization, washings, and detection steps were performed under stringent conditions. The following cell types of the rat and rabbit lung had abundant positive reaction product to the ETB probe: bronchiolar and bronchial epithelium, endothelium of smooth-muscle--walled vessels, and bronchial and bronchiolar-associated lymphoid tissue. Abundant positive reaction product was also observed in cell populations in the lung parenchyma. Additional studies are being performed to identify those populations. The results of this study suggest that in addition to vasoactivity, endothelins play other important roles in the lung.
Journal of Cardiovascular Pharmacology | 1993
Eddie C.-K. Liu; Hossain Monshizadegan; Chia-ching Chao; Jean S. Lynch; Susan M. Fisher; Patricia M. Rose; Maria L. Webb
Recent investigations have confirmed the presence of vasoconstrictory endothelinB (ETB) receptors in several tissues, including the rabbit saphenous vein (RSV). To determine the molecular nature of the ET receptor subtypes in RSV, radioligand-receptor binding with selective ligands was conducted. ET-1 inhibited 125I-ET-1 binding to RSV in a monophasic manner with an inhibition constant (Ki) of 0.08 +/- 0.03 nM. Inhibition of 125I-ET-1 binding by ET-3 or the ETA-selective peptide BQ-123 resulted in markedly biphasic inhibition curves with Ki values of 0.4 +/- 0.1 nM (36% of total sites)/37 +/- 10 nM (64% of total sites) for ET-3 and 10.4 +/- 1.9 nM (70%)/3.2 +/- 0.9 microM (30%) for BQ-123. The correspondence of high-affinity binding sites for BQ-123 with low-affinity binding sites for ET-3 agrees with the suggestion that 70% of the 125I-ET-1 binding sites in this tissue are ETA receptors. To further investigate the nature of the ET-B (non-ET-A) binding sites in RSV, 125I-ET-3 competition binding was conducted. ET-1 and BQ-123 inhibited 125I-ET-3 binding in RSV with Ki values of 40 +/- 7 pM and 7.2 microM, respectively, while ET-3 and the ETB receptor-selective agonist sarafotoxin S6c (S6c) inhibition curves were best fit to two-site models. Resultant Ki values for ET-3 and S6c were 50 pM (71%)/4 pM (29%) and 0.3 nM (76%)/115 nM (24%).(ABSTRACT TRUNCATED AT 250 WORDS)
Journal of Biological Chemistry | 1995
Patricia M. Rose; Prabhavathi Fernandes; Jean S. Lynch; Scott T. Frazier; Susan M. Fisher; Krishna Kodukula; Bernadette Kienzle; Ramakrishna Seethala
The Journal of Antibiotics | 1995
Pramathesh S. Patel; Stella Huang; Susan M. Fisher; Dolores M. Pirnik; Carol A. Aklonis; Loretta Dean; Edward Meyers; Prabhavathi Fernandes; Friedrich Mayerl
Journal of Biological Chemistry | 1994
S. R. Krystek; P. S. Patel; Patricia M. Rose; Susan M. Fisher; B. K. Kienzle; D. A. Lach; E. C.-K. Liu; Jean S. Lynch; J. Novotny; M. L. Webb
Biochemistry | 1996
Maria L. Webb; Pramathesh S. Patel; Patricia M. Rose; Eddie C.-K. Liu; Philip D. Stein; Joel C. Barrish; David A. Lach; Terry R. Stouch; Susan M. Fisher; Ophelia Hadjilambris; Helen Lee; S. Skwish; Kenneth E.J. Dickinson; Stanley R. Krystek
The Journal of Antibiotics | 1992
Joseph O'sullivan; Douglas W. Phillipson; Donald R. Kirsch; Susan M. Fisher; Margaret H. Lai; William H. Trejo
Molecular Pharmacology | 1993
Maria L. Webb; Eddie C.-K. Liu; Hossain Monshizadegan; Chia-ching Chao; Jean S. Lynch; Susan M. Fisher; Patricia M. Rose