Reciprocal Regulation of Aquaporin-2 Abundance and Degradation by Protein Kinase A and p38-MAP Kinase

Growth factor receptor tyrosine kinase regulation of the sequential phosphorylation reactions leading to mitogen-activated protein (MAP) kinase activation in PC12 cells has been investigated. In response to epidermal growth factor, nerve growth factor, and platelet-derived growth factor, B-Raf and Raf-1 are activated, phosphorylate recombinant kinase-inactive MEK-1, and activate wild-type MEK-1. MEK-1 is the dual-specificity protein kinase that selectively phosphorylates MAP kinase on tyrosine and threonine, resulting in MAP kinase activation. B-Raf and Raf-1 are growth factor-regulated Raf family members which regulate MEK-1 and MAP kinase activity in PC12 cells. Protein kinase A activation in response to elevated cyclic AMP (cAMP) levels inhibited B-Raf and Raf-1 stimulation in response to growth factors. Ras.GTP loading in response to epidermal growth factor, nerve growth factor, or platelet-derived growth factor was unaffected by protein kinase A activation. Even though elevated cAMP levels inhibited Raf activation, the growth factor activation of MEK-1 and MAP kinase was unaffected in PC12 cells. The results demonstrate that tyrosine kinase receptor activation of MEK-1 and MAP kinase in PC12 cells is regulated by B-Raf and Raf-1, whose activation is inhibited by protein kinase A, and MEK activators, whose activation is independent of cAMP regulation.

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B-Raf-dependent regulation of the MEK-1/mitogen-activated protein kinase pathway in PC12 cells and regulation by cyclic AMP.

Molecular and Cellular Biology ◽

10.1128/mcb.14.10.6522 ◽

1994 ◽

Vol 14 (10) ◽

pp. 6522-6530 ◽

Cited By ~ 128

Author(s):

R R Vaillancourt ◽

A M Gardner ◽

G L Johnson

Keyword(s):

Growth Factor ◽

Protein Kinase ◽

Map Kinase ◽

Protein Kinase A ◽

Pc12 Cells ◽

Kinase Activation ◽

Mitogen Activated Protein ◽

Epidermal Growth ◽

Camp Levels ◽

Kinase A

Growth factor receptor tyrosine kinase regulation of the sequential phosphorylation reactions leading to mitogen-activated protein (MAP) kinase activation in PC12 cells has been investigated. In response to epidermal growth factor, nerve growth factor, and platelet-derived growth factor, B-Raf and Raf-1 are activated, phosphorylate recombinant kinase-inactive MEK-1, and activate wild-type MEK-1. MEK-1 is the dual-specificity protein kinase that selectively phosphorylates MAP kinase on tyrosine and threonine, resulting in MAP kinase activation. B-Raf and Raf-1 are growth factor-regulated Raf family members which regulate MEK-1 and MAP kinase activity in PC12 cells. Protein kinase A activation in response to elevated cyclic AMP (cAMP) levels inhibited B-Raf and Raf-1 stimulation in response to growth factors. Ras.GTP loading in response to epidermal growth factor, nerve growth factor, or platelet-derived growth factor was unaffected by protein kinase A activation. Even though elevated cAMP levels inhibited Raf activation, the growth factor activation of MEK-1 and MAP kinase was unaffected in PC12 cells. The results demonstrate that tyrosine kinase receptor activation of MEK-1 and MAP kinase in PC12 cells is regulated by B-Raf and Raf-1, whose activation is inhibited by protein kinase A, and MEK activators, whose activation is independent of cAMP regulation.

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

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.90784.2008 ◽

2009 ◽

Vol 296 (2) ◽

pp. R419-R427 ◽

Cited By ~ 39

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.

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

AJP Renal Physiology ◽

10.1152/ajprenal.00376.2011 ◽

2012 ◽

Vol 302 (11) ◽

pp. F1395-F1401 ◽

Cited By ~ 37

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.

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Protein Kinase A Keeps MAP Kinase from the Nucleus

Science Signaling ◽

10.1126/stke.1999.13.tw4 ◽

1999 ◽

Vol 1999 (13) ◽

pp. tw4-tw4

Keyword(s):

Protein Kinase ◽

Map Kinase ◽

Protein Kinase A ◽

Kinase A

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

AJP Renal Physiology ◽

10.1152/ajprenal.00576.2020 ◽

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.

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