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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.
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MeSH Terms
Amphetamine actions at the serotonin transporter rely on the availability of phosphatidylinositol-4,5-bisphosphate.
Buchmayer F, Schicker K, Steinkellner T, Geier P, Stübiger G, Hamilton PJ, Jurik A, Stockner T, Yang JW, Montgomery T, Holy M, Hofmaier T, Kudlacek O, Matthies HJ, Ecker GF, Bochkov V, Galli A, Boehm S, Sitte HH
(2013) Proc Natl Acad Sci U S A 110: 11642-7
MeSH Terms: Amphetamine, HEK293 Cells, Humans, Phosphatidylinositol 4,5-Diphosphate, Second Messenger Systems, Serotonin Plasma Membrane Transport Proteins
Show Abstract · Added February 19, 2015
Nerve functions require phosphatidylinositol-4,5-bisphosphate (PIP2) that binds to ion channels, thereby controlling their gating. Channel properties are also attributed to serotonin transporters (SERTs); however, SERT regulation by PIP2 has not been reported. SERTs control neurotransmission by removing serotonin from the extracellular space. An increase in extracellular serotonin results from transporter-mediated efflux triggered by amphetamine-like psychostimulants. Herein, we altered the abundance of PIP2 by activating phospholipase-C (PLC), using a scavenging peptide, and inhibiting PIP2-synthesis. We tested the effects of the verified scarcity of PIP2 on amphetamine-triggered SERT functions in human cells. We observed an interaction between SERT and PIP2 in pull-down assays. On decreased PIP2 availability, amphetamine-evoked currents were markedly reduced compared with controls, as was amphetamine-induced efflux. Signaling downstream of PLC was excluded as a cause for these effects. A reduction of substrate efflux due to PLC activation was also found with recombinant noradrenaline transporters and in rat hippocampal slices. Transmitter uptake was not affected by PIP2 reduction. Moreover, SERT was revealed to have a positively charged binding site for PIP2. Mutation of the latter resulted in a loss of amphetamine-induced SERT-mediated efflux and currents, as well as a lack of PIP2-dependent effects. Substrate uptake and surface expression were comparable between mutant and WT SERTs. These findings demonstrate that PIP2 binding to monoamine transporters is a prerequisite for amphetamine actions without being a requirement for neurotransmitter uptake. These results open the way to target amphetamine-induced SERT-dependent actions independently of normal SERT function and thus to treat psychostimulant addiction.
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6 MeSH Terms
β-Cell-specific protein kinase A activation enhances the efficiency of glucose control by increasing acute-phase insulin secretion.
Kaihara KA, Dickson LM, Jacobson DA, Tamarina N, Roe MW, Philipson LH, Wicksteed B
(2013) Diabetes 62: 1527-36
MeSH Terms: Animals, Crosses, Genetic, Cyclic AMP, Cyclic AMP-Dependent Protein Kinases, Enzyme Induction, Exenatide, Glucose Clamp Technique, Hyperglycemia, Hypoglycemic Agents, Insulin, Insulin Secretion, Insulin-Secreting Cells, Kinetics, Mice, Mutant Proteins, Patch-Clamp Techniques, Peptides, Phosphorylation, Protein Processing, Post-Translational, Protein Subunits, Second Messenger Systems, Up-Regulation, Venoms
Show Abstract · Added February 12, 2015
Acute insulin secretion determines the efficiency of glucose clearance. Moreover, impaired acute insulin release is characteristic of reduced glucose control in the prediabetic state. Incretin hormones, which increase β-cell cAMP, restore acute-phase insulin secretion and improve glucose control. To determine the physiological role of the cAMP-dependent protein kinase (PKA), a mouse model was developed to increase PKA activity specifically in the pancreatic β-cells. In response to sustained hyperglycemia, PKA activity potentiated both acute and sustained insulin release. In contrast, a glucose bolus enhanced acute-phase insulin secretion alone. Acute-phase insulin secretion was increased 3.5-fold, reducing circulating glucose to 58% of levels in controls. Exendin-4 increased acute-phase insulin release to a similar degree as PKA activation. However, incretins did not augment the effects of PKA on acute-phase insulin secretion, consistent with incretins acting primarily via PKA to potentiate acute-phase insulin secretion. Intracellular calcium signaling was unaffected by PKA activation, suggesting that the effects of PKA on acute-phase insulin secretion are mediated by the phosphorylation of proteins involved in β-cell exocytosis. Thus, β-cell PKA activity transduces the cAMP signal to dramatically increase acute-phase insulin secretion, thereby enhancing the efficiency of insulin to control circulating glucose.
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23 MeSH Terms
Cell responses to growth factors: the role of receptor tyrosine kinase intracellular domain fragments.
Carpenter G, Pozzi A
(2012) Sci Signal 5: pe42
MeSH Terms: Cell Nucleus, Enzyme Activation, Gene Expression Regulation, Humans, Intercellular Signaling Peptides and Proteins, Models, Biological, Peptide Fragments, Receptor Protein-Tyrosine Kinases, Second Messenger Systems
Show Abstract · Added February 24, 2014
Growth factor activation of receptor tyrosine kinases (RTKs) provokes well-described canonical second messenger pathways that transmit biochemical signals in the cytoplasm and to the nucleus to initiate cellular responses. The proteolytic liberation of intracellular domain fragments (ICDs) from activated RTKs and the nuclear translocation of these ICDs represent a more recently identified and noncanonical mechanism by which RTKs communicate with the nucleus. Several reports have added previously unknown facets to the ICD mechanism and have enlarged the scope of ICDs as second messengers.
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9 MeSH Terms
Identification of key factors that reduce the variability of the single photon response.
Caruso G, Bisegna P, Andreucci D, Lenoci L, Gurevich VV, Hamm HE, DiBenedetto E
(2011) Proc Natl Acad Sci U S A 108: 7804-7
MeSH Terms: Animals, Calcium, Cyclic GMP, Light, Light Signal Transduction, Mice, Models, Biological, Photons, Retinal Rod Photoreceptor Cells, Rhodopsin, Rod Cell Outer Segment, Second Messenger Systems, Stochastic Processes
Show Abstract · Added December 10, 2013
Rod photoreceptors mediate vision in dim light. Their biological function is to discriminate between distinct, very low levels of illumination, i.e., they serve as reliable photon counters. This role requires high reproducibility of the response to a particular number of photons. Indeed, single photon responses demonstrate unexpected low variability, despite the stochastic nature of the individual steps in the transduction cascade. We analyzed individual system mechanisms to identify their contribution to variability suppression. These include: (i) cooperativity of the regulation of the second messengers; (ii) diffusion of cGMP and Ca(2+) in the cytoplasm; and (iii) the effect of highly localized cGMP hydrolysis by activated phosphodiesterase resulting in local saturation. We find that (i) the nonlinear relationships between second messengers and current at the plasma membrane, and the cGMP hydrolysis saturation effects, play a major role in stabilizing the system; (ii) the presence of a physical space where the second messengers move by Brownian motion contributes to stabilization of the photoresponse; and (iii) keeping Ca(2+) at its dark level has only a minor effect on the variability of the system. The effects of diffusion, nonlinearity, and saturation synergize in reducing variability, supporting the notion that the observed high fidelity of the photoresponse is the result of global system function of phototransduction.
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13 MeSH Terms
A closer look at amphetamine-induced reverse transport and trafficking of the dopamine and norepinephrine transporters.
Robertson SD, Matthies HJ, Galli A
(2009) Mol Neurobiol 39: 73-80
MeSH Terms: Amphetamine, Biological Transport, Diffusion, Dopamine, Dopamine Agents, Dopamine Plasma Membrane Transport Proteins, Humans, Norepinephrine Plasma Membrane Transport Proteins, Second Messenger Systems
Show Abstract · Added December 10, 2013
Amphetamine (AMPH) and its derivatives are regularly used in the treatment of a wide array of disorders such as attention-deficit hyperactivity disorder (ADHD), obesity, traumatic brain injury, and narcolepsy (Prog Neurobiol 75:406-433, 2005; J Am Med Assoc 105:2051-2054, 1935; J Am Acad Child Adolesc Psychiatry 41:514-521, 2002; Neuron 43:261-269, 2004; Annu Rev Pharmacol Toxicol 47:681-698, 2007; Drugs Aging 21:67-79, 2004). Despite the important medicinal role for AMPH, it is more widely known for its psychostimulant and addictive properties as a drug of abuse. The primary molecular targets of AMPH are both the vesicular monoamine transporters (VMATs) and plasma membrane monoamine-dopamine (DA), norepinephrine (NE), and serotonin (5-HT)-transporters. The rewarding and addicting properties of AMPH rely on its ability to act as a substrate for these transporters and ultimately increase extracellular levels of monoamines. AMPH achieves this elevation in extracellular levels of neurotransmitter by inducing synaptic vesicle depletion, which increases intracellular monoamine levels, and also by promoting reverse transport (efflux) through plasma membrane monoamine transporters (J Biol Chem 237:2311-2317, 1962; Med Exp Int J Exp Med 6:47-53, 1962; Neuron 19:1271-1283, 1997; J Physiol 144:314-336, 1958; J Neurosci 18:1979-1986, 1998; Science 237:1219-1223, 1987; J Neurosc 15:4102-4108, 1995). This review will focus on two important aspects of AMPH-induced regulation of the plasma membrane monoamine transporters-transporter mediated monoamine efflux and transporter trafficking.
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9 MeSH Terms
Rap1 activation is required for Fc gamma receptor-dependent phagocytosis.
Chung J, Serezani CH, Huang SK, Stern JN, Keskin DB, Jagirdar R, Brock TG, Aronoff DM, Peters-Golden M
(2008) J Immunol 181: 5501-9
MeSH Terms: Animals, Calcium, Cyclic AMP, Guanine Nucleotide-Releasing Factor 2, Humans, Immunologic Capping, Liposomes, Macrophages, Alveolar, Phagocytosis, Rats, Receptors, IgG, Second Messenger Systems, U937 Cells, rap1 GTP-Binding Proteins
Show Abstract · Added May 4, 2017
Phagocytosis of IgG-opsonized microbes via the Fc gamma receptor (Fc gammaR) requires the precise coordination of a number of signaling molecules, including the low-molecular mass GTPases. Little is known about the Ras-family GTPase Rap1 in this process. We therefore investigated its importance in mediating Fc gammaR-dependent phagocytosis in NR8383 rat alveolar macrophages. Pulldown of active Rap1 and fluorescence microscopic analysis of GFP-RalGDS (Ral guanine dissociation stimulator)-transfected macrophages revealed that Rap1 is indeed activated by Fc gammaR crosslinking. Inhibition of Rap1 activity, both by Rap1GAP (GTPase-activating protein) expression and liposome-delivered blocking Ab, severely impaired the ability of cells to ingest IgG-opsonized targets. Fc gammaR-induced Rap1 activation was found to be independent of both cAMP and Ca(2+), suggesting a role for the second messenger-independent guanosine exchange factor, C3G. This was supported by the facts that 1) liposome-delivered blocking Ab against C3G inhibited both Fc gammaR-dependent phagocytosis and Rap1 activation, and 2) both active Rap1GTP and C3G were found to translocate to the phagosome. Taken together, our data demonstrate a novel role for Rap1 and its exchange factor C3G in mediating Fc gammaR-dependent phagocytosis.
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14 MeSH Terms
Diffusion of the second messengers in the cytoplasm acts as a variability suppressor of the single photon response in vertebrate phototransduction.
Bisegna P, Caruso G, Andreucci D, Shen L, Gurevich VV, Hamm HE, DiBenedetto E
(2008) Biophys J 94: 3363-83
MeSH Terms: Animals, Calcium Signaling, Calibration, Catalysis, Cyclic GMP, Cytoplasm, Diffusion, Humans, Kinetics, Models, Biological, Photons, Second Messenger Systems, Time Factors, Vision, Ocular
Show Abstract · Added December 10, 2013
The single photon response in vertebrate phototransduction is highly reproducible despite a number of random components of the activation cascade, including the random activation site, the random walk of an activated receptor, and its quenching in a random number of steps. Here we use a previously generated and tested spatiotemporal mathematical and computational model to identify possible mechanisms of variability reduction. The model permits one to separate the process into modules, and to analyze their impact separately. We show that the activation cascade is responsible for generation of variability, whereas diffusion of the second messengers is responsible for its suppression. Randomness of the activation site contributes at early times to the coefficient of variation of the photoresponse, whereas the Brownian path of a photoisomerized rhodopsin (Rh*) has a negligible effect. The major driver of variability is the turnoff mechanism of Rh*, which occurs essentially within the first 2-4 phosphorylated states of Rh*. Theoretically increasing the number of steps to quenching does not significantly decrease the corresponding coefficient of variation of the effector, in agreement with the biochemical limitations on the phosphorylated states of the receptor. Diffusion of the second messengers in the cytosol acts as a suppressor of the variability generated by the activation cascade. Calcium feedback has a negligible regulatory effect on the photocurrent variability. A comparative variability analysis has been conducted for the phototransduction in mouse and salamander, including a study of the effects of their anatomical differences such as incisures and photoreceptors geometry on variability generation and suppression.
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14 MeSH Terms
Creation of a genetic model of obesity in a teleost.
Song Y, Cone RD
(2007) FASEB J 21: 2042-9
MeSH Terms: Agouti-Related Protein, Animals, Animals, Genetically Modified, Biological Evolution, Cyclic AMP, Disease Models, Animal, Energy Metabolism, Female, Gene Expression, Genes, Synthetic, Intercellular Signaling Peptides and Proteins, Leptin, Male, Melanocortins, Obesity, Promoter Regions, Genetic, Receptor, Melanocortin, Type 3, Receptor, Melanocortin, Type 4, Second Messenger Systems, Triglycerides, Zebrafish, Zebrafish Proteins
Show Abstract · Added December 10, 2013
The adipostat is the mechanism by which the brain detects and maintains constant levels of energy stored in adipocytes in the form of lipids. Key elements of the adipostat include the adipocyte-derived hormone leptin that is expressed in proportion to energy levels and serves to communicate this information to the central nervous system and the central circuits, which sense and respond to leptin. Blockade of one of these circuits, the central melanocortin system, disrupts leptin action and causes a distinct obesity syndrome in mice and humans, characterized by increased adiposity as well as increased linear growth. We show here that transgenic zebrafish overexpressing the endogenous melanocortin antagonist agouti-related protein (AgRP) also exhibit obesity, increased linear growth, and adipocyte hypertrophy. These findings demonstrate that key elements of the adipostat originated before the evolution of mammals. Furthermore, transgenic overexpression of AgRP in zebrafish yields a new model system for the genetic analysis of energy homeostasis in a simple vertebrate system.
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22 MeSH Terms
Characterization of immunoisolated human gastric parietal cells tubulovesicles: identification of regulators of apical recycling.
Lapierre LA, Avant KM, Caldwell CM, Ham AJ, Hill S, Williams JA, Smolka AJ, Goldenring JR
(2007) Am J Physiol Gastrointest Liver Physiol 292: G1249-62
MeSH Terms: Adult, Animals, Blotting, Western, Cells, Cultured, Chromatography, Liquid, Dogs, Female, H(+)-K(+)-Exchanging ATPase, Humans, Male, Middle Aged, Parietal Cells, Gastric, Proteome, SNARE Proteins, Second Messenger Systems, Tandem Mass Spectrometry, rab GTP-Binding Proteins
Show Abstract · Added October 7, 2013
Gastric parietal cells possess an amplified apical membrane recycling system dedicated to regulated apical recycling of H-K-ATPase. While amplified in parietal cells, apical recycling is critical to polarized secretory processes in most epithelial cells. To clarify putative regulators of apical recycling, we prepared immunoisolated parietal cell H-K-ATPase-containing recycling membranes from human stomachs and analyzed protein contents by tryptic digestion and mass spectrometry. We identified and validated by Western blots many of the proteins previously identified on immunoisolated rabbit tubulovesicles, including Rab11, Rab25, syntaxin 3, secretory carrier membrane proteins (SCAMPs), and vesicle-associated membrane protein (VAMP)2. In addition, we detected several previously unrecognized proteins, including Rab10, VAMP8, syntaxin 7, and syntaxin 12/13. We also identified the K(+) channel component KCNQ1. Immunostaining of human gastric mucosal sections confirmed the presence of each of these proteins in parietal cells and their colocalization with H-K-ATPase on tubulovesicles. To investigate the role of the identified soluble N-ethylmaleimide-sensitive factor attachment receptor (SNARE) proteins in apical recycling, we transfected them as DsRed2 fusions into an enhanced green fluorescent protein (EGFP)-Rab11a-expressing Madin-Darby canine kidney (MDCK) cell line. Syntaxin 12/13 and VAMP8 caused a collapse of the EGFP-Rab11a compartment, whereas a less dramatic effect was observed in cells transfected with syntaxin 3, syntaxin 7, or VAMP2. The five DsRed2-SNARE chimeras were also transfected into a MDCK cell line overexpressing Rab11-FIP2(129-512). All five of the chimeras were drawn into the collapsed apical recycling system. This study, which represents the first proteomic analysis of an immunoisolated vesicle population from native human tissue, demonstrates the diversity of putative regulators of the apical recycling system.
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17 MeSH Terms