scholarly journals cAMP Activates TRPC6 Channels via the Phosphatidylinositol 3-Kinase (PI3K)-Protein Kinase B (PKB)-Mitogen-activated Protein Kinase Kinase (MEK)-ERK1/2 Signaling Pathway

2011 ◽  
Vol 286 (22) ◽  
pp. 19439-19445 ◽  
Author(s):  
Bing Shen ◽  
Hiu-Yee Kwan ◽  
Xin Ma ◽  
Ching-On Wong ◽  
Juan Du ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Signaling Pathway ◽  
Single Channel ◽  
Mesangial Cells ◽  
Phosphorylation Site ◽  
Mitogen Activated Protein Kinase ◽  
Activation Mechanism ◽  
Hek293 Cells ◽  
Glomerular Mesangial Cells ◽  
Whole Cell

cAMP is an important second messenger that executes diverse physiological function in living cells. In this study, we investigated the effect of cAMP on canonical TRPC6 (transient receptor potential channel 6) channels in TRPC6-expressing HEK293 cells and glomerular mesangial cells. The results showed that 500 μm 8-Br-cAMP, a cell-permeable analog of cAMP, elicited [Ca2+]i increases and stimulated a cation current at the whole-cell level in TRPC6-expressing HEK293 cells. The effect of cAMP diminished in the presence of the PI3K inhibitors wortmannin and LY294002 or the MEK inhibitors PD98059, U0126, and MEK inhibitor I. 8-Br-cAMP also induced phosphorylation of MEK and ERK1/2. Conversion of serine to glycine at an ERK1/2 phosphorylation site (S281G) abolished the cAMP activation of TRPC6 as determined by whole-cell and cell-attached single-channel patch recordings. Experiments based on a panel of pharmacological inhibitors or activators suggested that the cAMP action on TRPC6 was not mediated by PKA, PKG, or EPAC (exchange protein activated by cAMP). Total internal fluorescence reflection microscopy showed that 8-Br-cAMP did not alter the trafficking of TRPC6 to the plasma membrane. We also found that, in glomerular mesangial cells, glucagon-induced [Ca2+]i increases were mediated through the cAMP-PI3K-PKB-MEK-ERK1/2-TRPC6 signaling pathway. In summary, this study uncovered a novel TRPC6 activation mechanism in which cAMP activates TRPC6 via the PI3K-PKB-MEK-ERK1/2 signaling pathway.

Protein kinase Cα participates in activation of store-operated Ca2+ channels in human glomerular mesangial cells

2002 ◽  
Vol 283 (5) ◽  
pp. C1390-C1398 ◽  
Author(s):  
Rong Ma ◽  
Patrick E. Kudlacek ◽  
Steven C. Sansom
Keyword(s):  
Protein Kinase ◽  
Intracellular Signaling ◽  
Single Channel ◽  
Mesangial Cells ◽  
Glomerular Mesangial Cells ◽  
Membrane Expression ◽  
Intracellular Signaling Pathway ◽  
Single Channel Analysis ◽  
Protein Kinase Cα ◽  
Channel Analysis

Protein kinase C (PKC) plays an important role in activating store-operated Ca2+ channels (SOC) in human mesangial cells (MC). The present study was performed to determine the specific isoform(s) of conventional PKC involved in activating SOC in MC. Fura 2 fluorescence ratiometry showed that the thapsigargin-induced Ca2+ entry (equivalent to SOC) was significantly inhibited by 1 μM Gö-6976 (a specific PKCα and βI inhibitor) and PKCα antisense treatment (2.5 nM for 24–48 h). However, LY-379196 (PKCβ inhibitor) and 2,2′,3,3′,4,4′-hexahydroxy-1,1′-biphenyl-6,6′-dimethanoldimethyl ether (HBDDE; PKCα and γ inhibitor) failed to affect thapsigargin-evoked activation of SOC. Single-channel analysis in the cell-attached configuration revealed that Gö-6976 and PKCα antisense significantly depressed thapsigargin-induced activation of SOC. However, LY-379196 and HBDDE did not affect the SOC responses. In inside-out patches, application of purified PKCα or βI, but not βII or γ, significantly rescued SOC from postexcision rundown. Western blot analysis revealed that thapsigargin evoked a decrease in cytosolic expression with a corresponding increase in membrane expression of PKCα and γ. However, the translocation from cytosol to membranes was not detected for PKCβI or βII. These results suggest that PKCα participates in the intracellular signaling pathway for activating SOC upon release of intracellular stores of Ca2+.

scholarly journals Cellular signaling by endothelin peptides: pathways to the nucleus.

1992 ◽  
Vol 2 (10) ◽  
pp. S116
Author(s):  
M S Simonson ◽  
Y Wang ◽  
M J Dunn
Keyword(s):  
Protein Kinase ◽  
Mesangial Cells ◽  
Regulatory Peptides ◽  
Mitogen Activated Protein Kinase ◽  
Activator Protein 1 ◽  
Glomerular Mesangial Cells ◽  
Short Term ◽  
Activator Protein ◽  
Mitogen Activated Protein

Endothelins (ET) are potent regulatory peptides that evoke diverse responses in glomerular mesangial cells. These include short-term actions, such as contraction and secretion, and long-term, adaptive responses, such as cell growth. Although much attention has been focused on the second messenger cascades, which govern short-term effects, the pathways of cytosolic and nuclear signaling, which effect long-term changes, remain unclear. Several distal signaling events by ET receptors have been characterized in rat mesangial cells. These include activation of a cytosolic protein kinase, mitogen-activated protein kinase and an inducible transcription factor, activator protein-1 (AP-1). This review focuses on the activation of mitogen-activated protein kinase and activator protein-1 by ET and discusses the potential role of these third and fourth messengers in controlling long-term cellular adaptations. Characterization of these and other cytosolic and nuclear signals should provide important insights into the pleiotropic actions of ET peptides.

scholarly journals Sphingolipid metabolites differentially regulate extracellular signal-regulated kinase and stress-activated protein kinase cascades

1996 ◽  
Vol 316 (1) ◽  
pp. 13-17 ◽  
Author(s):  
Emmaneul CORONEOS ◽  
Yizheng WANG ◽  
James R. PANUSKA ◽  
Dennis J. TEMPLETON ◽  
Mark KESTER
Keyword(s):  
Protein Kinase ◽  
Mesangial Cells ◽  
Membrane Receptors ◽  
Mitogen Activated Protein Kinase ◽  
Glomerular Mesangial Cells ◽  
Extracellular Signal Regulated Kinase ◽  
Mapk Signalling Pathway ◽  
Extracellular Signal ◽  
Mitogen Activated Protein ◽  
Plasma Membrane Receptors

The mitogen-activated protein kinase (MAPK) signalling pathway serves to translocate information from activated plasma-membrane receptors to initiate nuclear transcriptional events. This cascade has recently been subdivided into two analogous pathways: the extracellular signal-regulated kinase (ERK) cascade, which preferentially signals mitogenesis, and the stress-activated protein kinase (SAPK) cascade, which is linked to growth arrest and/or cellular inflammation. In concurrent experiments utilizing rat glomerular mesangial cells (MCs), we demonstrate that growth factors or sphingosine activate ERK but not SAPK. In contrast, inflammatory cytokines or cell-permeable ceramide analogues activate SAPK but not ERK. Ceramide, but not sphingosine, induces interleukin-6 secretion, a marker of an inflamed phenotype. Moreover, ceramide can suppress growth factor- or sphingosine-induced ERK activation as well as proliferation. These studies implicate sphingolipid metabolites as opposing regulators of cell proliferation and inflammation through activation of separate kinase cascades.

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