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Publication Record


Local, nonlinear effects of cGMP and Ca2+ reduce single photon response variability in retinal rods.
Caruso G, Gurevich VV, Klaus C, Hamm H, Makino CL, DiBenedetto E
(2019) PLoS One 14: e0225948
MeSH Terms: Algorithms, Animals, Biomarkers, Calcium, Cyclic GMP, Mice, Models, Biological, Photons, Retinal Rod Photoreceptor Cells, Rod Cell Outer Segment, Signal Transduction
Show Abstract · Added March 18, 2020
The single photon response (SPR) in vertebrate photoreceptors is inherently variable due to several stochastic events in the phototransduction cascade, the main one being the shutoff of photoactivated rhodopsin. Deactivation is driven by a random number of steps, each of random duration with final quenching occurring after a random delay. Nevertheless, variability of the SPR is relatively low, making the signal highly reliable. Several biophysical and mathematical mechanisms contributing to variability suppression have been examined by the authors. Here we investigate the contribution of local depletion of cGMP by PDE*, the non linear dependence of the photocurrent on cGMP, Ca2+ feedback by making use of a fully space resolved (FSR) mathematical model, applied to two species (mouse and salamander), by varying the cGMP diffusion rate severalfold and rod outer segment diameter by an order of magnitude, and by introducing new, more refined, and time dependent variability functionals. Globally well stirred (GWS) models, and to a lesser extent transversally well stirred models (TWS), underestimate the role of nonlinearities and local cGMP depletion in quenching the variability of the circulating current with respect to fully space resolved models (FSR). These distortions minimize the true extent to which SPR is stabilized by locality in cGMP depletion, nonlinear effects linking cGMP to current, and Ca2+ feedback arising from the physical separation of E* from the ion channels located on the outer shell, and the diffusion of these second messengers in the cytoplasm.
0 Communities
1 Members
0 Resources
11 MeSH Terms
Cardiac natriuretic peptides promote adipose 'browning' through mTOR complex-1.
Liu D, Ceddia RP, Collins S
(2018) Mol Metab 9: 192-198
MeSH Terms: Adipose Tissue, Brown, Animals, Atrial Natriuretic Factor, Cells, Cultured, Cyclic GMP-Dependent Protein Kinases, Female, HEK293 Cells, Humans, Male, Mechanistic Target of Rapamycin Complex 1, Mice, Mice, Inbred C57BL, Mitochondria, Signal Transduction, Uncoupling Protein 1
Show Abstract · Added September 25, 2018
OBJECTIVE - Activation of thermogenesis in brown adipose tissue (BAT) and the ability to increase uncoupling protein 1 (UCP1) levels and mitochondrial biogenesis in white fat (termed 'browning'), has great therapeutic potential to treat obesity and its comorbidities because of the net increase in energy expenditure. β-adrenergic-cAMP-PKA signaling has long been known to regulate these processes. Recently PKA-dependent activation of mammalian target of rapamycin complex 1 (mTORC1) was shown to be necessary for adipose 'browning' as well as proper development of the interscapular BAT. In addition to cAMP-PKA signaling pathways, cGMP-PKG signaling also promotes this browning process; however, it is unclear whether or not mTORC1 is also necessary for cGMP-PKG induced browning.
METHOD - Activation of mTORC1 by natriuretic peptides (NP), which bind to and activate the membrane-bound guanylyl cyclase, NP receptor A (NPRA), was assessed in mouse and human adipocytes in vitro and mouse adipose tissue in vivo.
RESULTS - Activation of mTORC1 by NP-cGMP signaling was observed in both mouse and human adipocytes. We show that NP-NPRA-PKG signaling activate mTORC1 by direct PKG phosphorylation of Raptor at Serine 791. Administration of B-type natriuretic peptide (BNP) to mice induced Ucp1 expression in inguinal adipose tissue in vivo, which was completely blocked by the mTORC1 inhibitor rapamycin.
CONCLUSION - Our results demonstrate that NP-cGMP signaling activates mTORC1 via PKG, which is a component in the mechanism of adipose browning.
Copyright © 2018 The Authors. Published by Elsevier GmbH.. All rights reserved.
0 Communities
2 Members
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15 MeSH Terms
Modulation of thalamocortical oscillations by TRIP8b, an auxiliary subunit for HCN channels.
Zobeiri M, Chaudhary R, Datunashvili M, Heuermann RJ, Lüttjohann A, Narayanan V, Balfanz S, Meuth P, Chetkovich DM, Pape HC, Baumann A, van Luijtelaar G, Budde T
(2018) Brain Struct Funct 223: 1537-1564
MeSH Terms: Action Potentials, Adenine, Adenylyl Cyclase Inhibitors, Animals, Cardiovascular Agents, Cerebral Cortex, Cyclic AMP, Cyclic GMP, Female, Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels, Male, Membrane Proteins, Mice, Mice, Inbred C57BL, Mice, Transgenic, Models, Neurological, Neural Pathways, Peroxins, Pyrimidines, Sodium Channel Blockers, Tetrodotoxin, Thalamus, Thionucleotides
Show Abstract · Added April 2, 2019
Hyperpolarization-activated cyclic nucleotide-gated cation (HCN) channels have important functions in controlling neuronal excitability and generating rhythmic oscillatory activity. The role of tetratricopeptide repeat-containing Rab8b-interacting protein (TRIP8b) in regulation of hyperpolarization-activated inward current, I , in the thalamocortical system and its functional relevance for the physiological thalamocortical oscillations were investigated. A significant decrease in I current density, in both thalamocortical relay (TC) and cortical pyramidal neurons was found in TRIP8b-deficient mice (TRIP8b). In addition basal cAMP levels in the brain were found to be decreased while the availability of the fast transient A-type K current, I , in TC neurons was increased. These changes were associated with alterations in intrinsic properties and firing patterns of TC neurons, as well as intrathalamic and thalamocortical network oscillations, revealing a significant increase in slow oscillations in the delta frequency range (0.5-4 Hz) during episodes of active-wakefulness. In addition, absence of TRIP8b suppresses the normal desynchronization response of the EEG during the switch from slow-wave sleep to wakefulness. It is concluded that TRIP8b is necessary for the modulation of physiological thalamocortical oscillations due to its direct effect on HCN channel expression in thalamus and cortex and that mechanisms related to reduced cAMP signaling may contribute to the present findings.
0 Communities
1 Members
0 Resources
MeSH Terms
Second messenger signaling mechanisms of the brown adipocyte thermogenic program: an integrative perspective.
Shi F, Collins S
(2017) Horm Mol Biol Clin Investig 31:
MeSH Terms: Adipocytes, Beige, Adipocytes, Brown, Animals, Cyclic AMP-Dependent Protein Kinases, Cyclic GMP-Dependent Protein Kinases, Energy Metabolism, Gene Expression Regulation, Humans, Intracellular Space, Mechanistic Target of Rapamycin Complex 1, MicroRNAs, Natriuretic Agents, RNA, Long Noncoding, Receptors, Adrenergic, beta, Second Messenger Systems, Signal Transduction, Thermogenesis, Uncoupling Protein 1
Show Abstract · Added September 26, 2018
β-adrenergic receptors (βARs) are well established for conveying the signal from catecholamines to adipocytes. Acting through the second messenger cyclic adenosine monophosphate (cAMP) they stimulate lipolysis and also increase the activity of brown adipocytes and the 'browning' of adipocytes within white fat depots (so-called 'brite' or 'beige' adipocytes). Brown adipose tissue mitochondria are enriched with uncoupling protein 1 (UCP1), which is a regulated proton channel that allows the dissipation of chemical energy in the form of heat. The discovery of functional brown adipocytes in humans and inducible brown-like ('beige' or 'brite') adipocytes in rodents have suggested that recruitment and activation of these thermogenic adipocytes could be a promising strategy to increase energy expenditure for obesity therapy. More recently, the cardiac natriuretic peptides and their second messenger cyclic guanosine monophosphate (cGMP) have gained attention as a parallel signaling pathway in adipocytes, with some unique features. In this review, we begin with some important historical work that touches upon the regulation of brown adipocyte development and physiology. We then provide a synopsis of some recent advances in the signaling cascades from β-adrenergic agonists and natriuretic peptides to drive thermogenic gene expression in the adipocytes and how these two pathways converge at a number of unexpected points. Finally, moving from the physiologic hormonal signaling, we discuss yet another level of control downstream of these signals: the growing appreciation of the emerging roles of non-coding RNAs as important regulators of brown adipocyte formation and function. In this review, we discuss new developments in our understanding of the signaling mechanisms and factors including new secreted proteins and novel non-coding RNAs that control the function as well as the plasticity of the brown/beige adipose tissue as it responds to the energy needs and environmental conditions of the organism.
0 Communities
2 Members
0 Resources
MeSH Terms
Selective depletion of vascular EC-SOD augments chronic hypoxic pulmonary hypertension.
Nozik-Grayck E, Woods C, Taylor JM, Benninger RK, Johnson RD, Villegas LR, Stenmark KR, Harrison DG, Majka SM, Irwin D, Farrow KN
(2014) Am J Physiol Lung Cell Mol Physiol 307: L868-76
MeSH Terms: Animals, Blood Pressure, Cyclic GMP, Cyclic Nucleotide Phosphodiesterases, Type 5, Estrogen Antagonists, GTP Cyclohydrolase, Guanylate Cyclase, Hypertension, Pulmonary, Hypertrophy, Right Ventricular, Hypoxia, Lung, Mice, Mice, Knockout, Nitric Oxide Synthase Type III, Pulmonary Artery, Receptors, Cytoplasmic and Nuclear, Signal Transduction, Soluble Guanylyl Cyclase, Superoxide Dismutase, Tamoxifen
Show Abstract · Added March 31, 2015
Excess superoxide has been implicated in pulmonary hypertension (PH). We previously found lung overexpression of the antioxidant extracellular superoxide dismutase (EC-SOD) attenuates PH and pulmonary artery (PA) remodeling. Although comprising a small fraction of total SOD activity in most tissues, EC-SOD is abundant in arteries. We hypothesize that the selective loss of vascular EC-SOD promotes hypoxia-induced PH through redox-sensitive signaling pathways. EC-SOD(loxp/loxp) × Tg(cre/SMMHC) mice (SMC EC-SOD KO) received tamoxifen to conditionally deplete smooth muscle cell (SMC)-derived EC-SOD. Mice were exposed to hypobaric hypoxia for 35 days, and PH was assessed by right ventricular systolic pressure measurements and right ventricle hypertrophy. Vascular remodeling was evaluated by morphometric analysis and two-photon microscopy for collagen. We examined cGMP content and soluble guanylate cyclase expression and activity in lung, lung phosphodiesterase 5 (PDE5) expression and activity, and expression of endothelial nitric oxide synthase and GTP cyclohydrolase-1 (GTPCH-1), the rate-limiting enzyme in tetrahydrobiopterin synthesis. Knockout of SMC EC-SOD selectively decreased PA EC-SOD without altering total lung EC-SOD. PH and vascular remodeling induced by chronic hypoxia was augmented in SMC EC-SOD KO. Depletion of SMC EC-SOD did not impact content or activity of lung soluble guanylate cyclase or PDE5, yet it blunted the hypoxia-induced increase in cGMP. Although total eNOS was not altered, active eNOS and GTPCH-1 decreased with hypoxia only in SMC EC-SOD KO. We conclude that the localized loss of PA EC-SOD augments chronic hypoxic PH. In addition to oxidative inactivation of NO, deletion of EC-SOD seems to reduce eNOS activity, further compromising pulmonary vascular function.
Copyright © 2014 the American Physiological Society.
1 Communities
2 Members
0 Resources
20 MeSH Terms
Nitrite therapy improves left ventricular function during heart failure via restoration of nitric oxide-mediated cytoprotective signaling.
Bhushan S, Kondo K, Polhemus DJ, Otsuka H, Nicholson CK, Tao YX, Huang H, Georgiopoulou VV, Murohara T, Calvert JW, Butler J, Lefer DJ
(2014) Circ Res 114: 1281-91
MeSH Terms: Aged, Animals, Biological Availability, Cyclic GMP, Cytoprotection, Disease Models, Animal, Female, Heart Failure, Hemodynamics, Humans, MAP Kinase Signaling System, Male, Mice, Mice, Inbred C57BL, Middle Aged, Nitric Oxide, Signal Transduction, Sodium Nitrite, Stroke Volume, Ventricular Dysfunction, Left
Show Abstract · Added January 29, 2016
RATIONALE - Nitric oxide (NO) bioavailability is reduced in the setting of heart failure. Nitrite (NO2) is a critically important NO intermediate that is metabolized to NO during pathological states. We have previously demonstrated that sodium nitrite ameliorates acute myocardial ischemia/reperfusion injury.
OBJECTIVE - No evidence exists as to whether increasing NO bioavailability via nitrite therapy attenuates heart failure severity after pressure-overload-induced hypertrophy.
METHODS AND RESULTS - Serum from patients with heart failure exhibited significantly decreased nitrosothiol and cGMP levels. Transverse aortic constriction was performed in mice at 10 to 12 weeks. Sodium nitrite (50 mg/L) or saline vehicle was administered daily in the drinking water postoperative from day 1 for 9 weeks. Echocardiography was performed at baseline and at 1, 3, 6, and 9 weeks after transverse aortic constriction to assess left ventricular dimensions and ejection fraction. We observed increased cardiac nitrite, nitrosothiol, and cGMP levels in mice treated with nitrite. Sodium nitrite preserved left ventricular ejection fraction and improved left ventricular dimensions at 9 weeks (P<0.001 versus vehicle). In addition, circulating and cardiac brain natriuretic peptide levels were attenuated in mice receiving nitrite (P<0.05 versus vehicle). Western blot analyses revealed upregulation of Akt-endothelial nitric oxide-nitric oxide-cGMP-GS3Kβ signaling early in the progression of hypertrophy and heart failure.
CONCLUSIONS - These results support the emerging concept that nitrite therapy may be a viable clinical option for increasing NO levels and may have a practical clinical use in the treatment of heart failure.
0 Communities
1 Members
0 Resources
20 MeSH Terms
Differential activation of natriuretic peptide receptors modulates cardiomyocyte proliferation during development.
Becker JR, Chatterjee S, Robinson TY, Bennett JS, Panáková D, Galindo CL, Zhong L, Shin JT, Coy SM, Kelly AE, Roden DM, Lim CC, MacRae CA
(2014) Development 141: 335-45
MeSH Terms: Animals, Animals, Genetically Modified, Atrial Natriuretic Factor, Cell Proliferation, Cyclic AMP, Cyclic GMP-Dependent Protein Kinases, Gene Knockdown Techniques, Heart, Myocytes, Cardiac, Natriuretic Peptide, Brain, Receptors, Atrial Natriuretic Factor, Signal Transduction, Zebrafish, Zebrafish Proteins
Show Abstract · Added February 19, 2015
Organ development is a highly regulated process involving the coordinated proliferation and differentiation of diverse cellular populations. The pathways regulating cell proliferation and their effects on organ growth are complex and for many organs incompletely understood. In all vertebrate species, the cardiac natriuretic peptides (ANP and BNP) are produced by cardiomyocytes in the developing heart. However, their role during cardiogenesis is not defined. Using the embryonic zebrafish and neonatal mammalian cardiomyocytes we explored the natriuretic peptide signaling network during myocardial development. We observed that the cardiac natriuretic peptides ANP and BNP and the guanylate cyclase-linked natriuretic peptide receptors Npr1 and Npr2 are functionally redundant during early cardiovascular development. In addition, we demonstrate that low levels of the natriuretic peptides preferentially activate Npr3, a receptor with Gi activator sequences, and increase cardiomyocyte proliferation through inhibition of adenylate cyclase. Conversely, high concentrations of natriuretic peptides reduce cardiomyocyte proliferation through activation of the particulate guanylate cyclase-linked natriuretic peptide receptors Npr1 and Npr2, and activation of protein kinase G. These data link the cardiac natriuretic peptides in a complex hierarchy modulating cardiomyocyte numbers during development through opposing effects on cardiomyocyte proliferation mediated through distinct cyclic nucleotide signaling pathways.
0 Communities
2 Members
0 Resources
14 MeSH Terms
Atrial natriuretic peptide is negatively regulated by microRNA-425.
Arora P, Wu C, Khan AM, Bloch DB, Davis-Dusenbery BN, Ghorbani A, Spagnolli E, Martinez A, Ryan A, Tainsh LT, Kim S, Rong J, Huan T, Freedman JE, Levy D, Miller KK, Hata A, Del Monte F, Vandenwijngaert S, Swinnen M, Janssens S, Holmes TM, Buys ES, Bloch KD, Newton-Cheh C, Wang TJ
(2013) J Clin Invest 123: 3378-82
MeSH Terms: 3' Untranslated Regions, Adult, Animals, Atrial Natriuretic Factor, COS Cells, Chlorocebus aethiops, Cyclic GMP, Female, Gene Expression, Gene Frequency, Genetic Association Studies, Humans, Hypertension, Male, MicroRNAs, Polymorphism, Single Nucleotide, RNA Interference, Sequence Analysis, DNA, Sodium Chloride, Dietary, Young Adult
Show Abstract · Added April 15, 2014
Numerous common genetic variants have been linked to blood pressure, but no underlying mechanism has been elucidated. Population studies have revealed that the variant rs5068 (A/G) in the 3' untranslated region of NPPA, the gene encoding atrial natriuretic peptide (ANP), is associated with blood pressure. We selected individuals on the basis of rs5068 genotype (AG vs. AA) and fed them a low- or high-salt diet for 1 week, after which they were challenged with an intravenous saline infusion. On both diets, before and after saline administration, ANP levels were up to 50% higher in AG individuals than in AA individuals, a difference comparable to the changes induced by high-salt diet or saline infusion. In contrast, B-type natriuretic peptide levels did not differ by rs5068 genotype. We identified a microRNA, miR-425, that is expressed in human atria and ventricles and is predicted to bind the sequence spanning rs5068 for the A, but not the G, allele. miR-425 silenced NPPA mRNA in an allele-specific manner, with the G allele conferring resistance to miR-425. This study identifies miR-425 as a regulator of ANP production, raising the possibility that miR-425 antagonists could be used to treat disorders of salt overload, including hypertension and heart failure.
0 Communities
1 Members
0 Resources
20 MeSH Terms
Single molecule analysis of serotonin transporter regulation using antagonist-conjugated quantum dots reveals restricted, p38 MAPK-dependent mobilization underlying uptake activation.
Chang JC, Tomlinson ID, Warnement MR, Ustione A, Carneiro AM, Piston DW, Blakely RD, Rosenthal SJ
(2012) J Neurosci 32: 8919-29
MeSH Terms: Actins, Animals, Cell Line, Transformed, Cholera Toxin, Cholesterol, Cyclic GMP, Cytochalasin D, Enzyme Inhibitors, Gangliosidosis, GM1, Imidazoles, Ligands, Membrane Microdomains, Microscopy, Confocal, Neurons, Normal Distribution, Nucleic Acid Synthesis Inhibitors, Protein Transport, Pyridines, Quantum Dots, Rats, Serotonin, Serotonin Plasma Membrane Transport Proteins, Thionucleotides, beta-Cyclodextrins, p38 Mitogen-Activated Protein Kinases
Show Abstract · Added November 8, 2013
The presynaptic serotonin (5-HT) transporter (SERT) is targeted by widely prescribed antidepressant medications. Altered SERT expression or regulation has been implicated in multiple neuropsychiatric disorders, including anxiety, depression and autism. Here, we implement a generalizable strategy that exploits antagonist-conjugated quantum dots (Qdots) to monitor, for the first time, single SERT proteins on the surface of serotonergic cells. We document two pools of SERT proteins defined by lateral mobility, one that exhibits relatively free diffusion, and a second, localized to cholesterol and GM1 ganglioside-enriched microdomains, that displays restricted mobility. Receptor-linked signaling pathways that enhance SERT activity mobilize transporters that, nonetheless, remain confined to membrane microdomains. Mobilization of transporters arises from a p38 MAPK-dependent untethering of the SERT C terminus from the juxtamembrane actin cytoskeleton. Our studies establish the utility of ligand-conjugated Qdots for analysis of the behavior of single membrane proteins and reveal a physical basis for signaling-mediated SERT regulation.
1 Communities
5 Members
0 Resources
25 MeSH Terms
A cyclic guanosine monophosphate-dependent pathway can regulate net hepatic glucose uptake in vivo.
An Z, Winnick JJ, Moore MC, Farmer B, Smith M, Irimia JM, Roach PJ, Cherrington AD
(2012) Diabetes 61: 2433-41
MeSH Terms: Animals, Blood Pressure, Cyclic AMP, Cyclic GMP, Dogs, Glucagon, Glucose, Glycogen Phosphorylase, Glycogen Synthase, Insulin, Liver, Portal Vein, Signal Transduction
Show Abstract · Added June 2, 2014
We previously showed that hepatic nitric oxide regulates net hepatic glucose uptake (NHGU), an effect that can be eliminated by inhibiting hepatic soluble guanylate cyclase (sGC), suggesting that the sGC pathway is involved in the regulation of NHGU. The aim of the current study was to determine whether hepatic cyclic guanosine monophosphate (cGMP) reduces NHGU. Studies were performed on conscious dogs with transhepatic catheters. A hyperglycemic-hyperinsulinemic clamp was established in the presence of portal vein glucose infusion. 8-Br-cGMP (50 µg/kg/min) was delivered intraportally, and either the glucose load to the liver (CGMP/GLC; n = 5) or the glucose concentration entering the liver (CGMP/GCC; n = 5) was clamped at 2× basal. In the control group, saline was given intraportally (SAL; n = 10), and the hepatic glucose concentration and load were doubled. 8-Br-cGMP increased portal blood flow, necessitating the two approaches to glucose clamping in the cGMP groups. NHGU (mg/kg/min) was 5.8 ± 0.5, 2.7 ± 0.5, and 4.8 ± 0.3, whereas the fractional extraction of glucose was 11.0 ± 1, 5.5 ± 1, and 8.5 ± 1% during the last hour of the study in SAL, CGMP/GLC, and CGMP/GCC, respectively. The reduction of NHGU in response to 8-Br-cGMP was associated with increased AMP-activated protein kinase phosphorylation. These data indicate that changes in liver cGMP can regulate NHGU under postprandial conditions.
0 Communities
3 Members
1 Resources
13 MeSH Terms