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Full-Text Articles in Cell Biology

Reversal Of P-Glycoprotein And Breast Cancer Resistance Protein Mediated Multidrug Resistance In Vitro Using In Silico Identified Novel Compounds, Amila Nanayakkara May 2019

Reversal Of P-Glycoprotein And Breast Cancer Resistance Protein Mediated Multidrug Resistance In Vitro Using In Silico Identified Novel Compounds, Amila Nanayakkara

Biological Sciences Theses and Dissertations

Multidrug resistance (MDR) is a major cause of chemotherapy failure. Overexpression of ATP-binding cassette (ABC) transporters, P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) are two well-studied drug transporters which are associated with MDR. These two transporters also act as a major functional unit of the blood brain barrier to protect the brain from xenobiotics and toxins. Lack of clinically approved P-gp and BCRP inhibitors renders chemotherapy treatments of many MDR cancers ineffective and obstructs drug uptake into the brain.

Using computational methods, we have identified new compounds that inhibit P-gp (Brewer et al., Mol. Pharmacol. 2014). Several of these ...


Reversal Of P-Glycoprotein And Breast Cancer Resistance Protein Mediated Multidrug Resistance In Vitro Using In Silico Identified Novel Compounds, Amila Nanayakkara May 2019

Reversal Of P-Glycoprotein And Breast Cancer Resistance Protein Mediated Multidrug Resistance In Vitro Using In Silico Identified Novel Compounds, Amila Nanayakkara

Biological Sciences Theses and Dissertations

Multidrug resistance (MDR) is a major cause of chemotherapy failure. Overexpression of ATP-binding cassette (ABC) transporters, P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) are two well-studied drug transporters which are associated with MDR. These two transporters also act as a major functional unit of the blood brain barrier to protect the brain from xenobiotics and toxins. Lack of clinically approved P-gp and BCRP inhibitors renders chemotherapy treatments of many MDR cancers ineffective and obstructs drug uptake into the brain.

Using computational methods, we have identified new compounds that inhibit P-gp (Brewer et al., Mol. Pharmacol. 2014). Several of these ...


Epidermal Growth Factor-Like Ligands Regulate Dimer Selection., Jamie S. Rush Dec 2018

Epidermal Growth Factor-Like Ligands Regulate Dimer Selection., Jamie S. Rush

Electronic Theses and Dissertations

There are thirteen known endogenous EGF-like ligands. We previously reported that Betacellulin (BTC) increases ligand-mediated corneal wound healing more than Epidermal Growth Factor (EGF) [Peterson et al. (2014) IOVS 55(5):2870-80], although the molecular reason for this is unknown. Despite being better at promoting wound healing via enhanced cell migration, BTC has reduced receptor affinity and weaker induction of EGFR phosphorylation. These data indicate that BTC’s response is not due to enhanced affinity or EGFR-kinase activity. Receptor phosphorylation and proximity ligation assays indicate that BTC treatment significantly increases ErbB3 phosphorylation and EGFR:ErbB3 heterodimers. BTC traffics EGFR at ...


Egfr Signaling From The Early Endosome., Julie A. Gosney Aug 2018

Egfr Signaling From The Early Endosome., Julie A. Gosney

Electronic Theses and Dissertations

The epidermal growth factor receptor (EGFR) is a receptor tyrosine kinase that is an integral component of proliferative signaling. When activated by a ligand at the plasma membrane, EGFR dimerizes with another ErbB family receptor, leading to kinase domain activation and transphosphorylation of C-terminus tyrosine residues. These phosphotyrosines act as crucial regulators of EGFR signaling as effector proteins dock to the receptor at these sites. The receptor undergoes clathrin-mediated endocytosis into early endosomes, where it can then be trafficked to a lysosome for degradation. However, the kinase domain of EGFR retains its activity during trafficking, suggesting that EGFR can continue ...


Investigation Of P-Glycoprotein (Pgp) Induction By Pgp Substrates To Induce Paclitaxel Resistance In Ovarian Cancer Cells, Ryker Penn May 2018

Investigation Of P-Glycoprotein (Pgp) Induction By Pgp Substrates To Induce Paclitaxel Resistance In Ovarian Cancer Cells, Ryker Penn

Theses & Dissertations

The purpose of this study was to investigate the development of chemotherapeutic resistance to paclitaxel in ovarian cancer cells after treatment with drugs that are substrates for P-glycoprotein (PGP). A core concept of this experiment was to identify if PGP substrate drugs could also act as PGP inducers after prolonged treatment in SKOV-3 ovarian cancer cells. In order to test this, SKOV-3 cells were exposed to either fexofenadine, a PGP substrate used as an antihistamine, or the chemotherapeutic drug vinblastine. After 42 days of drug treatment, ABCB1 gene expression was measured by qRT-PCR. Analysis of ABCB1 expression in treated cells ...


Pharmacologic And Genetic Manipulations Of Angiotensin Signaling In Thoracic Aortic Disease Models, Andrew M. Peters Aug 2017

Pharmacologic And Genetic Manipulations Of Angiotensin Signaling In Thoracic Aortic Disease Models, Andrew M. Peters

UT GSBS Dissertations and Theses (Open Access)

Thoracic aortic aneurysms and dissections (TAAD) are a major cause of morbidity and mortality in patients. Many different risk factors have been associated TAAD, but hypertension is the largest risk factor. Subsets of TAAD patients have identifiable syndromic genetic diseases, yet a number of genetic non-syndromic patients have been identified. Infusion of angiotensin II into mouse models causes aortic disease through inflammation and fibrosis. An angiotensin type I receptor (AT1R) blocker (ARB) or an angiotensin converting enzyme (ACE) inhibitor (ACEi) can reverse aortic pathology in some mouse models. I set out to better understand the relationship between angiotensin and TAAD ...


Defining Sites Of Replication Fork Collapse Caused By Atr Inhibition, Nishita Kalpendu Shastri Jan 2017

Defining Sites Of Replication Fork Collapse Caused By Atr Inhibition, Nishita Kalpendu Shastri

Publicly Accessible Penn Dissertations

DEFINING SITES OF REPLICATION FORK COLLAPSE CAUSED BY ATR INHIBITION

Nishita K. Shastri

Eric J. Brown

Replication stress, characterized by stalling of DNA replication and the accumulation of abnormal replication intermediates, has been linked to the genomic instability observed in cancer. Previous studies have defined specific genomic sequences that are difficult to replicate to be more vulnerable to replication-associated breaks and rearrangements. However, many of these sequences have been identified through indirect and potentially biased approaches. To identify DNA sequences that contribute to replication-associated genomic instability, I will describe genome-wide screens I have performed to determine the location, sequence, and ...


Extracellular Matrix Regulates Fibroblast Heterogeneity And Tumorigenesis, Diana Leigh Avery Jan 2017

Extracellular Matrix Regulates Fibroblast Heterogeneity And Tumorigenesis, Diana Leigh Avery

Publicly Accessible Penn Dissertations

Heterogeneous activated fibroblasts that deposit and remodel extracellular matrix (ECM) comprise desmoplasia, a key regulator of tumor development. The divergent outcomes in response to varied therapies targeting intratumoral desmoplasia underscore the pressing need to delineate the intricate role of a heterogeneous stroma in tumorigenesis. Fibroblast activation protein (FAP) and alpha-smooth muscle actin (αSMA) identify distinct, yet overlapping, activated fibroblast subsets in myriad tumor types, fibrosis, and wound healing. FAPHi reactive fibroblasts and αSMAHi myofibroblasts can exert divergent influences on tumor progression. However, the factors that drive this phenotypic heterogeneity and the unique functional roles of these distinct phenotypes are not ...


Salvianolic Acid B For Pulmonary Delivery Towards Reversal Of Emphysema, Sneha Dhapare Jan 2017

Salvianolic Acid B For Pulmonary Delivery Towards Reversal Of Emphysema, Sneha Dhapare

Theses and Dissertations

A new pathobiologic hypothesis has recently emerged that the alveolar structural destruction and loss in emphysema are caused by the deficiency of vascular endothelial growth factor (VEGF). Therefore, this project hypothesized that such pathobiologic VEGF deficiency of emphysematous lungs can be recovered with a natural caffeic acid tetramer, salvianolic acid B (SalB), through activation of signal transducer and activator of transcription 3 (STAT3), so that emphysema can be reversed as a result of inhibition of induced cell death, stimulation of cell proliferation and migration, and promotion of stem cell recruitment to the lungs.

SalB was first shown to be potently ...


Changes In Threonyl-Trna Synthetase Expression And Secretion In Response To Endoplasmic Reticulum Stress By Monensin In Ovarian Cancer Cells, Jared Louis Hammer Jan 2017

Changes In Threonyl-Trna Synthetase Expression And Secretion In Response To Endoplasmic Reticulum Stress By Monensin In Ovarian Cancer Cells, Jared Louis Hammer

Graduate College Dissertations and Theses

Aminoacyl-tRNA synthetases (ARS) are a family of enzymes that catalyze the charging of amino acids to their cognate tRNA in an aminoacylation reaction. Many members of this family have been found to have secondary functions independent of their primary aminoacylation function. Threonyl-tRNA synthetase (TARS), the ARS responsible for charging tRNA with threonine, is secreted from endothelial cells in response to both vascular endothelial growth factor (VEGF) and tumor necrosis factor-α (TNF-α), and stimulates angiogenesis and cell migration. Here we show a novel experimental approach for studying TARS secretion, and for observing the role of intracellular TARS in the endoplasmic reticulum ...


Development Of Cellular High Throughput Assays To Determine The Electrophysiological Profile Of Gaba(A) Receptor Modulators For Neurology And Immunology, Nina Yina Yuan Aug 2016

Development Of Cellular High Throughput Assays To Determine The Electrophysiological Profile Of Gaba(A) Receptor Modulators For Neurology And Immunology, Nina Yina Yuan

Theses and Dissertations

Gamma (γ) -aminobutyric acid (GABA) is the major inhibitory neurotransmitter found in

the mammalian central nervous system. Its effect stems from its ability to cause the opening of ion channels which causes an influx of negatively charged chloride ions or an efflux of positively charged potassium ions. This hyperpolarization of the neuron lowers the threshold for neuronal firing. This has an overall inhibitory effect on neurotransmission, decreasing the excitability of the neuron and diminishing the likelihood of a successful action potential occurring. There are two classes of GABA receptor: ligand-gated GABAA receptor (GABAAR) and metabotropic GABAB receptor (GABABR). The GABAAR ...


Isolation Of Egfr-Containing Early Endosomes., Julie A. Gosney Aug 2016

Isolation Of Egfr-Containing Early Endosomes., Julie A. Gosney

Electronic Theses and Dissertations

The epidermal growth factor receptor (EGFR) is a receptor tyrosine kinase (RTK) that is an integral component of proliferative signaling. When activated by a ligand at the plasma membrane, EGFR undergoes clathrin-mediated endocytosis. This spatial regulation of the receptor is an important regulator of receptor expression as it mediates its degradation. Endocytosis also has implications on EGFR downstream signaling, though the details are not fully understood. The goal of this thesis is to develop a method to isolate early endosomes in order to study downstream effectors associated with activated EGFR in this compartment. HeLa cells were used to test various ...


Phosphoproteomic Characterization Of Glycogen Synthase Kinase-3, Mansi Shinde Jan 2016

Phosphoproteomic Characterization Of Glycogen Synthase Kinase-3, Mansi Shinde

Publicly Accessible Penn Dissertations

Glycogen Synthase Kinase-3 (GSK-3) is a constitutively active, ubiquitously expressed kinase that acts as a critical regulator of many signaling pathways. These pathways, when dysregulated, have been implicated in many human diseases, including bipolar disorder (BD), cancer, and diabetes. Over 100 putative GSK-3 substrates have been reported, based on direct kinase assays or genetic and pharmacological manipulation of GSK-3, in diverse cell types. Many more have been predicted based upon on the prevalence of the GSK-3 consensus sequence. As a result, there remains an unclear picture of the complete GSK-3 phosphoproteome. We have therefore used a large-scale mass spectrometry approach ...


Normal Glycolytic Enzyme Activity Is Critical For Hypoxia Inducible Factor-1a Activity And Provides Novel Targets For Inhibiting Tumor Growth, Geoffrey Grandjean Phd Dec 2015

Normal Glycolytic Enzyme Activity Is Critical For Hypoxia Inducible Factor-1a Activity And Provides Novel Targets For Inhibiting Tumor Growth, Geoffrey Grandjean Phd

UT GSBS Dissertations and Theses (Open Access)

Normal Glycolytic Enzyme Activity is Critical for Hypoxia Inducible Factor-1α Activity and Provides Novel Targets for Inhibiting Tumor Growth

By Geoffrey Grandjean

Advisory Professor: Garth Powis, D. Phil

Unique to proliferating cancer cells is the observation that their increased need for energy is provided by a high rate of glycolysis followed by lactic acid fermentation in a process known as the Warburg Effect, a process many times less efficient than oxidative phosphorylation employed by normal cells to satisfy a similar energy demand [1]. This high rate of glycolysis occurs regardless of the concentration of oxygen in the cell and is ...


Eicosapentaenoic Acid (Epa) From Porphyridium Cruentum: Increasing Growth And Productivity Of The Microalgae For Pharmaceutical Products, Maryam Asgharpour Dec 2015

Eicosapentaenoic Acid (Epa) From Porphyridium Cruentum: Increasing Growth And Productivity Of The Microalgae For Pharmaceutical Products, Maryam Asgharpour

Theses and Dissertations

One of the major nutritional requirements in our diet is an adequate intake of omega-3 specially eicosapentaenoic acid (EPA). In the present study, the effects of two temperatures (16°C & 20˚C) and light intensities (140 & 180µE/M2.S) and four nitrate levels (0.075, 0.3, 0.5 and 0.7g/L) on the cell growth and lipid productivity of Porphyridium cruentum, one of the most promising oil-rich species of microalgae, were investigated. A growth comparison was carried out using pure CO2 and 5% CO2/air. Additionally, the ratio of the fatty acids with omega-3 and omega-6 groups at ...


Pemetrexed, A Modulator Of Amp-Activated Kinase Signaling And An Inhibitor Of Wild Type And Mutant P53, Stuti Agarwal Jan 2015

Pemetrexed, A Modulator Of Amp-Activated Kinase Signaling And An Inhibitor Of Wild Type And Mutant P53, Stuti Agarwal

Theses and Dissertations

New drug discoveries and new approaches towards diagnosis and treatment have improved cancer therapeutics remarkably. One of the most influential and effective discoveries in the field of cancer therapeutics was antimetabolites, such as the antifolates. The interest in antifolates increased as some of the antifolates showed responses in cancers, such as mesothelioma, leukemia, and breast cancers. When pemetrexed (PTX) was discovered, our laboratory had established that the primary mechanism of action of pemetrexed is to inhibit thymidylate 22 synthase (TS) (E. Taylor et al., 1992). Preclinical studies have shown that PTX has a broad range of antitumor activity in human ...


Proteasome Inhibition As A Potential Anti-Breast Cancer Therapy: Mechanisms Of Action And Resistance-Reversing Strategies, Rahul Rajesinh Deshmukh Jan 2015

Proteasome Inhibition As A Potential Anti-Breast Cancer Therapy: Mechanisms Of Action And Resistance-Reversing Strategies, Rahul Rajesinh Deshmukh

Wayne State University Dissertations

AMPK activation and Ubiquitin Proteasome System (UPS) inhibition have gained great attention as therapeutic strategies for the treatment of certain types of cancers. While AMPK serves as a master regulator of cellular metabolism, UPS regulates protein homeostasis. Although the crosstalk between them is suggested, the relationship between these two important pathways is not very clear. We observed that proteasome inhibition leads to AMPK activation in human breast cancer cells. We report that a variety of proteasome inhibitors activate AMPK in all of the tested cancer cell lines. Our data using Liver Kinase B1 (LKB1)-deficient cancer cells suggests that proteasome ...


Characterization Of A Non-Canonical Function For Threonyl-Trna Synthetase In Angiogenesis, Adam Christopher Mirando Jan 2015

Characterization Of A Non-Canonical Function For Threonyl-Trna Synthetase In Angiogenesis, Adam Christopher Mirando

Graduate College Dissertations and Theses

In addition to its canonical role in aminoacylation, threonyl-tRNA synthetase (TARS) possesses pro-angiogenic activity that is susceptible to the TARS-specific antibiotic borrelidin. However, the therapeutic benefit of borrelidin is offset by its strong toxicity to living cells. The removal of a single methylene group from the parent borrelidin generates BC194, a modified compound with significantly reduced toxicity but comparable anti-angiogenic potential. Biochemical analyses revealed that the difference in toxicities was due to borrelidin's stimulation of amino acid starvation at ten-fold lower concentrations than BC194. However, both compounds were found to inhibit in vitro and in vivo models of angiogenesis ...


Dj-1 And Atp13a2: Two Proteins Involved In Parkinson’S Disease, Josephat M Asiago Jan 2014

Dj-1 And Atp13a2: Two Proteins Involved In Parkinson’S Disease, Josephat M Asiago

Open Access Dissertations

Parkinson's disease (PD) is the second most common neurodegenerative disorder after Alzheimer's disease, affecting approximately 0.3% of the total U.S. population, and its prevalence increases with age. Two neuropathological hallmarks of PD are the loss of dopaminergic neurons in the substantia nigra pars compacta, a region in the midbrain involved in initiating and sustaining movement, and the presence of cytosolic inclusions called Lewy bodies (LBs) in various brain regions. LBs are enriched with fibrillar forms of the presynaptic protein &agr;-synuclein (aSyn). Two autosomal recessive genes implicated in familial PD are PARK9, encoding the P-type ATPase ATP13A2 ...


Role Of Ceramide Kinase In Breast Cancer Progression, Ania Warczyk Payne Jan 2014

Role Of Ceramide Kinase In Breast Cancer Progression, Ania Warczyk Payne

Publicly Accessible Penn Dissertations

Recurrent breast cancer is typically an incurable disease and, as such, is disproportionately responsible for deaths from this disease. Recurrent breast cancers arise from the pool of disseminated tumor cells (DTCs) that survive adjuvant or neoadjuvant therapy, and patients with detectable DTCs following therapy are at substantially increased risk for recurrence. Consequently, the identification of pathways that contribute to the survival of breast cancer cells following therapy could aid in the development of more effective therapies that decrease the burden of residual disease and thereby reduce the risk of breast cancer recurrence. We now report that Ceramide Kinase (Cerk) is ...


Mechanisms Of Cyclooxygenase-2-Dependent Human Aortic Smooth Muscle Cell Phenotypic Modulation, Oreoluwa O. Adedoyin Jan 2014

Mechanisms Of Cyclooxygenase-2-Dependent Human Aortic Smooth Muscle Cell Phenotypic Modulation, Oreoluwa O. Adedoyin

Theses and Dissertations--Pharmacy

Abdominal aortic aneurysm (AAA) is a disease of the aorta characterized by pathological remodeling and progressive weakening of the vessel resulting in the increased risk of rupture and sudden death. In a mouse model of the disease induced by chronic Angiotensin II (AngII) infusion, progression of AAAs is associated with reduced differentiation of smooth muscle cells (SMCs) at the site of lesion development. In the mouse model, the effectiveness of cyclooxygenase-2 (COX-2) inhibition for attenuating AAA progression is associated with maintenance of a differentiated SMC phenotype. However, the safety of COX-2 inhibitors is currently in question due to the increased ...


The Multifunctional Protein Daxx: Studies Of Its Biology And Regulation, And Discovery Of A Novel Function, Trisha Agrawal Jan 2013

The Multifunctional Protein Daxx: Studies Of Its Biology And Regulation, And Discovery Of A Novel Function, Trisha Agrawal

Publicly Accessible Penn Dissertations

Daxx, a multifunctional protein with a diverse set of proposed functions, is ubiquitously expressed and highly conserved through evolution. A primarily nuclear protein, Daxx is able to regulate apoptosis, transcription, and cellular proliferation. Despite many studies into the function of Daxx, its precise role in the cell remains enigmatic. Herein, evidence is presented to expand upon the known anti-apoptotic function of Daxx, to establish Daxx as a novel molecular chaperone, and to further its repertoire of transcriptional targets. As an apoptotic inhibitor, Daxx is known to regulate p53 by stabilizing its main negative regulator, Mdm2, via formation of a ternary ...


Acidic Pericellular Ph: Effects On Proteolysis And Gene Expression As Determined In 3d Models Of Breast Carcinoma, Jennifer M. Rothberg Jan 2013

Acidic Pericellular Ph: Effects On Proteolysis And Gene Expression As Determined In 3d Models Of Breast Carcinoma, Jennifer M. Rothberg

Wayne State University Dissertations

Among the non-cellular microenvironmental factors that contribute to malignancy of solid tumors is an acidic peritumoral pH. The first objective was to determine if an acidic extracellular pH observed in vivo (i.e., pHe 6.8) affects the activity of proteases, such as cathepsin B, that contribute to degradation of collagen IV by tumor cells when grown in biologically relevant three-dimensional cultures. At pHe 6.8 there were increases in pericellular active cysteine cathepsins and in degradation of DQ-collagen IV, which was partially blocked by a cathepsin B inhibitor. Imaging probes for active cysteine cathepsins localized to tumors in vivo ...


Modelling Β2ar Regulation, Sharat J. Vayttaden Dec 2011

Modelling Β2ar Regulation, Sharat J. Vayttaden

UT GSBS Dissertations and Theses (Open Access)

The β2 adrenergic receptor (β2AR) regulates smooth muscle relaxation in the vasculature and airways. Long- and Short-acting β-agonists (LABAs/SABAs) are widely used in treatment of chronic obstructive pulmonary disorder (COPD) and asthma. Despite their widespread clinical use we do not understand well the dominant β2AR regulatory pathways that are stimulated during therapy and bring about tachyphylaxis, which is the loss of drug effects. Thus, an understanding of how the β2AR responds to various β-agonists is crucial to their rational use. Towards that end we have developed deterministic models that explore the mechanism of drug- induced β2AR regulation. These mathematical ...


Role Of Rap Signaling In The Regulation Of Erk Activation And Cell-Cell Adhesion, Lisa A. Vuchak May 2011

Role Of Rap Signaling In The Regulation Of Erk Activation And Cell-Cell Adhesion, Lisa A. Vuchak

Publicly Accessible Penn Dissertations

Rap is a member of the Ras family of small GTPases. Mammalian Rap proteins regulate many biological processes including cell and matrix adhesion, migration, proliferation, cytoskeletal dynamics, cell polarity and secretion. Rap1 is activated by TSH and cAMP in thyroid cells independently of PKA. TSH regulates differentiated gene expression and proliferation. Many of these effects are mediated through PKA. There is disagreement as to whether cAMP signaling through Rap contributes to any of the cellular effects of TSH. Given that thyroid cells express high levels of B-Raf and that Rap1 activates ERK through B-Raf in many cells, we investigated whether ...


Compensatory Mechanisms Of Neuroprotection By Pkd Signaling Against Oxidative Damage In Experimental Models Of Parkinson's Disease (Pd): Relevance To Pd Drug Discovery Strategies, Arunkumar Asaithambi Jan 2011

Compensatory Mechanisms Of Neuroprotection By Pkd Signaling Against Oxidative Damage In Experimental Models Of Parkinson's Disease (Pd): Relevance To Pd Drug Discovery Strategies, Arunkumar Asaithambi

Graduate Theses and Dissertations

Oxidative stress is a key pathophysiological mechanism contributing to the selective degeneration of dopaminergic neurons in Parkinson's disease. Unraveling the molecular mechanisms underlying various stages of oxidative neuronal damage is critical to better understanding the diseases and developing new treatment modalities. In this study, we identified that protein kinase D1 (PKD1) functions as a key anti-apoptotic kinase to protect neuronal cells against early stages of oxidative stress. Blockade of PKCδ cleavage, PKCδ knockdown or overexpression of a cleavage-resistant PKCδ mutant effectively attenuated PKD1 activation, indicating that PKCδ proteolytic activation regulates PKD1 phosphorylation. We also identified that phosphorylation of S916 ...


Identification Of A Conserved Cluster In The Rh Domain Of Grk Critical For Activation By Gpcrs, Faiza Baameur Dec 2009

Identification Of A Conserved Cluster In The Rh Domain Of Grk Critical For Activation By Gpcrs, Faiza Baameur

UT GSBS Dissertations and Theses (Open Access)

One of the most critical aspects of G Protein Coupled Receptors (GPCRs) regulation is their rapid and acute desensitization following agonist stimulation. Phosphorylation of these receptors by GPCR kinases (GRK) is a major mechanism of desensitization. Considerable evidence from studies of rhodopsin kinase and GRK2 suggests there is an allosteric docking site for the receptor distinct from the GRK catalytic site. While the agonist-activated GPCR appears crucial for GRK activation, the molecular details of this interaction remain unclear. Recent studies suggested an important role for the N- and C-termini and domains in the small lobe of the kinase domain in ...


Mechanisms Of Somatostatin-Induced Paradoxical Increase In Insulin Secretion In The Presence Of Arginine Vasopressin In Clonal [Beta]-Cell Hit-T15 , Henrique Cheng Jan 2002

Mechanisms Of Somatostatin-Induced Paradoxical Increase In Insulin Secretion In The Presence Of Arginine Vasopressin In Clonal [Beta]-Cell Hit-T15 , Henrique Cheng

Retrospective Theses and Dissertations

We investigated the mechanism underlying somatostatin-induced increase in [Ca2+]i leading to insulin release in the presence of arginine vasopressin (AVP) in clonal beta-cell HIT-T15. Somatostatin increased [Ca2+]i and insulin release in a biphasic pattern, characterized by a sharp and transient increase followed by a rapid decline to the sub-basal level. Pretreatment with pertussis toxin, which inactivates Gi/Go, abolished the effects of somatostatin. U-73122, an inhibitor of phospholipase C, antagonized somatostatin-induced increase in [Ca2+] i. In Ca2+-free environment, somatostatin still increased [Ca2+]i, whereas depletion of intracellular Ca 2+ stores with thapsigargin, a microsomal Ca2+ ATPase inhibitor ...


Comparison Of Beta-Adrenoceptor Coupled Camp Production In Cultured Human Mononuclear Leukocytes And Myometrial Cells, Yu-Li Liu Dec 1997

Comparison Of Beta-Adrenoceptor Coupled Camp Production In Cultured Human Mononuclear Leukocytes And Myometrial Cells, Yu-Li Liu

Electronic Theses and Dissertations

$\beta\sb2$-Adrenoceptor ($\beta\sb2$-AR) agonists, such as terbutaline, are used as tocolytic agents in the treatment of preterm labor. $\beta$-Adrenoceptor stimulation relaxes myometrium through specific receptors coupled through Gs to adenylyl cyclase (AC) that catalyzes the conversion of ATP to cAMP. The purpose of this study was to compare $\beta$-adrenoceptors and cAMP production in cultured human leukocytes and myometrial cells, and to determine the importance of $\beta$-adrenoceptors and cAMP production in isoproterenol-induced myometrial relaxation. $\sp{125}$I-iodopindolol was used to assess $\beta$-adrenoceptor affinity and number cAMP levels were analyzed before and after stimulation by ...


Utilization Of Fatigued And Non-Fatigued Isolated Guinea-Pig Papillary Muscles And Ventricular Myocytes On The Comparison Of Inotropic, Chronotropic And Intracellular Calcium Changes Induced By Monensin And Digoxin , Ismail Meral Jan 1996

Utilization Of Fatigued And Non-Fatigued Isolated Guinea-Pig Papillary Muscles And Ventricular Myocytes On The Comparison Of Inotropic, Chronotropic And Intracellular Calcium Changes Induced By Monensin And Digoxin , Ismail Meral

Retrospective Theses and Dissertations

Experiment 1. We investigated the effects of monensin and digoxin on contraction force (CF), initial contraction velocity (ICV), average contraction velocity (ACV), initial relaxation velocity (IRV) and stimulus to response time (ST) change in fatigued (defined as the level at which papillary muscle contraction had lost 30% of its original contraction force with the elapse of time) and non-fatigued guinea-pig papillary muscles. The five hours of measurement in Experiment 3 were divided into five periods (T0 was equilibration, T1, T2, T3, and T4 were respectively one, two, three, and four hours after drug administration). We found that both monensin and ...