scholarly journals Regulation of the Molecular Shuttle Service: A Multiscale Model of Aquaporin 2 Recycling

2021 ◽  
Author(s):  
Christoph Leberecht ◽  
Michael Schroeder ◽  
Dirk Labudde
Keyword(s):  
Protein Kinase ◽  
Protein Kinase A ◽  
Cellular Response ◽  
Multiscale Model ◽  
Cellular Systems ◽  
The Body ◽  
Aquaporin 2 ◽  
Messenger Molecules ◽  
Molecular Shuttle ◽  
Kinase A

The response of cells to their environment is driven by a variety of proteins and messenger molecules. In eukaryotes their distribution, which is regulated by a vesicular transport system, is important for a tight cellular response. The recycling of aquaporin 2 between membrane and storage region is a crucial part of the body water homeostasis and its malfunction can lead to Diabetes insipidus. To understand the regulation of this system, we aggregated pathways and mechanisms from literature and derived three models in a hypothesis-driven approach. Furthermore, we combined the models to a single system to gain insight into key regulatory mechanisms. To achieve this we developed a multiscale computational framework for the modeling and simulation of cellular systems. The analysis of the system rationalises that the compartmentalization of cAMP in renal principal cells is a result of the protein kinase A signalosome and can only occur if specific cellular components are observed in conjunction. Endocytotic and exocytotic processes are inherently connected and can be regulated by the same protein kinase A signal.

scholarly journals ATP and adenosine in the local regulation of water transport and homeostasis by the kidney

2009 ◽  
Vol 296 (2) ◽  
pp. R419-R427 ◽  
Author(s):  
Timo Rieg ◽  
Volker Vallon
Keyword(s):  
Protein Kinase ◽  
Protein Kinase A ◽  
Water Transport ◽  
Water Permeability ◽  
Apical Cell ◽  
Apical Cell Membrane ◽  
Local Factors ◽  
Aquaporin 2 ◽  
Potential Interactions ◽  
Kinase A

Regulation of body water homeostasis is critically dependent on the kidney and under the control of AVP, which is released from the neurohypophysis. In the collecting duct (CD) of the kidney, AVP activates adenylyl cyclase via vasopressin V2 receptors. cAMP-dependent activation of protein kinase A phosphorylates the water channel aquaporin-2 and increases water permeability by insertion of aquaporin-2 into the apical cell membrane. However, local factors modulate the effects of AVP to fine tune its effects, accelerate responses, and potentially protect the integrity of CD cells. Nucleotides like ATP belong to these local factors and act in an autocrine and paracrine way to activate P2Y2 receptors on CD cells. Extracellular breakdown of ATP and cAMP forms adenosine, the latter also induces specific effects on the CD by activation of adenosine A1 receptors. Activation of both receptor types can inhibit the cAMP-triggered activation of protein kinase A and reduce water permeability and transport. This review focuses on the role and potential interactions of the ATP and adenosine system with regard to the regulation of water transport in the CD. We address the potential stimuli and mechanisms involved in nucleotide release and adenosine formation, and discuss the corresponding signaling cascades that are activated. Potential interactions between the ATP and adenosine system, as well as other factors involved in the regulation of CD function, are outlined. Data from pharmacological studies and gene-targeted mouse models are presented to demonstrate the in vivo relevance to water transport and homeostasis.

In mpkCCD cells, long-term regulation of aquaporin-2 by vasopressin occurs independent of protein kinase A and CREB but may involve Epac

2012 ◽  
Vol 302 (11) ◽  
pp. F1395-F1401 ◽  
Author(s):  
Marleen L. A. Kortenoeven ◽  
Christiane Trimpert ◽  
Michiel van den Brand ◽  
Yuedan Li ◽  
Jack F. M. Wetzels ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Protein Kinase A ◽  
Collecting Duct ◽  
Urine Concentration ◽  
Creb Phosphorylation ◽  
Aquaporin 2 ◽  
Element Binding Protein ◽  
Responsive Element ◽  
Kinase A

Urine concentration involves the hormone vasopressin (AVP), which stimulates cAMP production in renal principal cells, resulting in translocation and transcription of aquaporin-2 (AQP2) water channels, greatly increasing the water permeability, leading to a concentrated urine. As cAMP levels decrease shortly after AVP addition, whereas AQP2 levels still increase and are maintained for days, we investigated in the present study the mechanism responsible for the AQP2 increase after long-term 1-desamino-8-d-arginine vasopressin (dDAVP) application using mouse collecting duct (mpkCCD) cells. While 30 min of dDAVP incubation strongly increased cAMP, cAMP was lower with 1 day and was even further reduced with 4 days of dDAVP, although still significantly higher than in control cells. One day of dDAVP incubation increased AQP2 promoter-dependent transcription, which was blocked by the protein kinase A (PKA) inhibitor H89. Moreover, phosphorylation of the cAMP-responsive element binding protein (CREB) and CRE-dependent transcription was observed after short-term dDAVP stimulation. With 4 days of dDAVP, AQP2 transcription remained elevated, but this was not blocked by H89, and CRE-dependent transcription and CREB phosphorylation were not increased. Exchange factor directly activated by cAMP (Epac) 1 and 2 were found to be endogenously expressed in mpkCCD cells. Application of dDAVP increased the expression of Epac1, while Epac2 was reduced. Incubation with a specific Epac activator after dDAVP pretreatment increased both AQP2 abundance and transcription compared with cells left unstimulated the last day. In conclusion, the PKA-CRE pathway is involved in the initial rise in AQP2 levels after dDAVP stimulation but not in the long-term effect of dDAVP. Instead, long-term regulation of AQP2 may involve the activation of Epac.

scholarly journals Protein Kinase Inhibitor Peptide as a Tool to Specifically Inhibit Protein Kinase A

2020 ◽  
Vol 11 ◽  
Author(s):  
Chong Liu ◽  
Ping Ke ◽  
Jingjing Zhang ◽  
Xiaoying Zhang ◽  
Xiongwen Chen
Keyword(s):  
Protein Kinase ◽  
Protein Kinase A ◽  
Kinase Inhibitor ◽  
Cyclic Adenosine Monophosphate ◽  
Adenosine Monophosphate ◽  
Protein Kinase Inhibitor ◽  
The Body ◽  
Specific Method ◽  
Inhibitor Peptide ◽  
Kinase A

The protein kinase enzyme family plays a pivotal role in almost every aspect of cellular function, including cellular metabolism, division, proliferation, transcription, movement, and survival. Protein kinase A (PKA), whose activation is triggered by cyclic adenosine monophosphate (cAMP), is widely distributed in various systems and tissues throughout the body and highly related to pathogenesis and progression of various kinds of diseases. The inhibition of PKA activation is essential for the study of PKA functions. Protein kinase inhibitor peptide (PKI) is a potent, heat-stable, and specific PKA inhibitor. It has been demonstrated that PKI can block PKA-mediated phosphorylase activation. Since then, researchers have a lot of knowledge about PKI. PKI is considered to be the most effective and specific method to inhibit PKA and is widely used in related research. In this review, we will first introduce the knowledge on the activation of PKA and mechanisms related on the inhibitory effects of PKI on PKA. Then, we will compare PKI-mediated PKA inhibition vs. several popular methods of PKA inhibition.

Psychotropic drugs upregulate aquaporin-2 via vasopressin-2 receptor/cAMP/protein kinase A signaling in inner medullary collecting duct cells

2021 ◽  
Author(s):  
Sua Kim ◽  
Chor Ho Jo ◽  
Gheun-Ho Kim
Keyword(s):  
Protein Kinase ◽  
Protein Expression ◽  
Protein Kinase A ◽  
Psychotropic Drugs ◽  
Collecting Duct ◽  
Camp Production ◽  
Inner Medullary Collecting Duct ◽  
Aquaporin 2 ◽  
Medullary Collecting Duct ◽  
Kinase A

Psychotropic drugs may be associated with hyponatremia, but an understanding of how they induce water retention in the kidney remains elusive. Previous studies have postulated that they may increase vasopressin production in the hypothalamus without supporting evidences. In this study, we investigated the possibility of drug-induced nephrogenic syndrome of inappropriate antidiuresis (NSIAD) using haloperidol, sertraline, and carbamazepine. Haloperidol, sertraline, or carbamazepine were treated in inner medullary collecting duct (IMCD) suspensions and primary cultured IMCD cells prepared from male Sprague-Dawley rats. The responses of intracellular cAMP production, aquaporin-2 (AQP2) protein expression and localization, vasopressin-2 receptor (V2R) and AQP2 mRNA, and cAMP-responsive element binding protein (CREB) were tested with and without tolvaptan, and the protein kinase A (PKA) inhibitors H89 and Rp-cAMPS. In IMCD suspensions, cAMP production was increased by haloperidol, sertraline, or carbamazepine and was relieved by tolvaptan cotreatment. In primary cultured IMCD cells, haloperidol, sertraline, or carbamazepine treatment increased total-AQP2 and decreased pSer261-AQP2 protein expression. Notably, these responses were reversed by cotreatment with tolvaptan or a PKA inhibitor. AQP2 membrane trafficking was induced by haloperidol, sertraline, or carbamazepine and was also blocked by cotreatment with tolvaptan or a PKA inhibitor. Furthermore, upregulation of V2R and AQP2 mRNA and phosphorylated CREB was induced by haloperidol, sertraline, or carbamazepine and was blocked by tolvaptan cotreatment. We conclude that, in the rat IMCD, psychotropic drugs upregulate AQP2 via V2R-cAMP-PKA signaling in the absence of vasopressin stimulation. The vasopressin-like action on the kidney appears to accelerate AQP2 transcription and dephosphorylate AQP2 at serine 261.

Direct effect of protein kinase A on four putative phosphorylation sites of aquaporin 2 in vitro

2020 ◽  
Vol 525 (2) ◽  
pp. 505-511
Author(s):  
Zhiyi Chen ◽  
Jieqiu Zhuang ◽  
Qing Yang ◽  
Jianhuan Yang ◽  
Dexuan Wang ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Protein Kinase A ◽  
Direct Effect ◽  
Phosphorylation Sites ◽  
Aquaporin 2 ◽  
Kinase A

scholarly journals Protein Kinase A Anchoring Proteins Are Required for Vasopressin-mediated Translocation of Aquaporin-2 into Cell Membranes of Renal Principal Cells

1999 ◽  
Vol 274 (8) ◽  
pp. 4934-4938 ◽  
Author(s):  
Enno Klussmann ◽  
Kenan Maric ◽  
Burkhard Wiesner ◽  
Michael Beyermann ◽  
Walter Rosenthal
Keyword(s):  
Protein Kinase ◽  
Protein Kinase A ◽  
Cell Membranes ◽  
Principal Cells ◽  
Aquaporin 2 ◽  
Anchoring Proteins ◽  
Kinase A

Snf1 protein kinase: a key player in the response to cellular stress in yeast

2003 ◽  
Vol 31 (1) ◽  
pp. 178-181 ◽  
Author(s):  
P. Sanz
Keyword(s):  
Gene Expression ◽  
Protein Kinase ◽  
Protein Kinase A ◽  
Transcriptional Activation ◽  
Cellular Response ◽  
Main Role ◽  
Snf1 Kinase ◽  
Amp Activated Protein Kinase ◽  
Broad Role ◽  
Kinase A

Sucrose non-fermenting 1 (Snf1) protein kinase, a yeast homologue of mammalian AMP-activated protein kinase, plays a main role in transcriptional activation and repression of gene expression. In addition, Snf1 kinase has a broad role in the cellular response to several forms of stress, such as nutrient limitation, salt stress and heat shock.

scholarly journals Integration of Stress Responses: Modulation of Calcineurin Signaling in Saccharomyces cerevisiae by Protein Kinase A

2004 ◽  
Vol 3 (5) ◽  
pp. 1147-1153 ◽  
Author(s):  
Kimberly A. Kafadar ◽  
Martha S. Cyert
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Protein Kinase ◽  
Protein Kinase A ◽  
Stress Responses ◽  
Nuclear Import ◽  
Cellular Response ◽  
Dependent Protein ◽  
Kinase A

ABSTRACT Calcineurin is a Ca2+/calmodulin-dependent protein phosphatase required for Saccharomyces cerevisiae to adapt to a variety of environmental stresses. Once activated, calcineurin dephosphorylates the Zn-finger transcription factor Crz1p/Tcn1p, causing it to accumulate in the nucleus where it activates gene expression. Here we show that cyclic AMP-dependent protein kinase A (PKA) phosphorylates and negatively regulates Crz1p activity by inhibiting its nuclear import. Activation of PKA in vivo decreases Crz1p-dependent transcription. PKA phosphorylates Crz1p in vitro, and we identify specific residues required for this phosphorylation, all of which reside in or adjacent to the nuclear localization signal. Mutation of these residues to alanine results in increased nuclear import of Crz1p and results in higher levels of both basal and Ca2+-induced Crz1p transcriptional activity. PKA regulates the general stress response in yeast and coordinates this response with nutrient availability. In contrast, calcineurin regulates the cellular response to a restricted set of environmental insults. Thus, these studies identify a specific biochemical mechanism through which the activities of multiple stress-activated signaling pathways are integrated in vivo.

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