PDGF-stimulated cyclic AMP formation in airway smooth muscle: assessment of the roles of MAP kinase, cytosolic phospholipase A2, and arachidonate metabolites

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Abstract

Platelet-derived growth factor (PDGF) stimulates cyclic AMP (cAMP) synthesis in cultured guinea-pig airway smooth muscle (ASM) cells. However, this stimulation is normally countered by the action of cAMP phosphodiesterases. Thus, cAMP synthesis was observed only in cells pre-treated with either 3-isobutyl-1-methylxanthine (IBMX) or with cholera toxin. cAMP synthesis was inhibited by pre-treating cells with well-defined inhibitors of arachidonate metabolite synthesis, such as AACOCF3 [a cytosolic phospholipase A2 (cPLA2) inhibitor] and indomethacin (a cyclooxygenase inhibitor). This suggests that arachidonate metabolites (e.g., prostaglandins) released in response to PDGF stimulate cAMP synthesis. The presence of functional prostaglandin (PG) receptors was confirmed by experiments that showed that exogenous PGE2 stimulated cAMP formation. cPLA2 is regulated by mitogen-activated protein kinase (MAPK) in a number of cell types. The presence of this pathway in ASM cells and its role in regulating arachidonate metabolism were supported by the finding that pre-treatment of cells with PD098059 (an inhibitor of mitogen-activated protein kinase kinase-1 activation) reduced PDGF-stimulated cAMP synthesis. The cAMP formed in response to the arachidonate metabolites subsequently reduced the PDGF-dependent activation of c-Raf, MAPK, and DNA synthesis, suggesting the presence of a negative feedback pathway.
LanguageEnglish
Pages363-369
Number of pages7
JournalCellular Signalling
Volume10
Issue number5
DOIs
Publication statusPublished - May 1998

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Cytosolic Phospholipases A2
Platelet-Derived Growth Factor
Cyclic AMP
Smooth Muscle
Phosphotransferases
Mitogen-Activated Protein Kinases
Smooth Muscle Myocytes
MAP Kinase Kinase 1
Prostaglandin Receptors
1-Methyl-3-isobutylxanthine
Cyclooxygenase Inhibitors
Cholera Toxin
Phosphoric Diester Hydrolases
Dinoprostone
Indomethacin
Prostaglandins
Guinea Pigs
Cell Count

Keywords

  • animals
  • arachidonic acid
  • calcium-calmodulin-dependent protein kinases
  • cells, cultured
  • cyclic AMP
  • cytosolic
  • DNA
  • guinea pigs
  • Muscle, Smooth
  • phospholipases A
  • phospholipases A2
  • platelet-derived growth factor
  • prostaglandin-endoperoxide synthases

Cite this

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title = "PDGF-stimulated cyclic AMP formation in airway smooth muscle: assessment of the roles of MAP kinase, cytosolic phospholipase A2, and arachidonate metabolites",
abstract = "Platelet-derived growth factor (PDGF) stimulates cyclic AMP (cAMP) synthesis in cultured guinea-pig airway smooth muscle (ASM) cells. However, this stimulation is normally countered by the action of cAMP phosphodiesterases. Thus, cAMP synthesis was observed only in cells pre-treated with either 3-isobutyl-1-methylxanthine (IBMX) or with cholera toxin. cAMP synthesis was inhibited by pre-treating cells with well-defined inhibitors of arachidonate metabolite synthesis, such as AACOCF3 [a cytosolic phospholipase A2 (cPLA2) inhibitor] and indomethacin (a cyclooxygenase inhibitor). This suggests that arachidonate metabolites (e.g., prostaglandins) released in response to PDGF stimulate cAMP synthesis. The presence of functional prostaglandin (PG) receptors was confirmed by experiments that showed that exogenous PGE2 stimulated cAMP formation. cPLA2 is regulated by mitogen-activated protein kinase (MAPK) in a number of cell types. The presence of this pathway in ASM cells and its role in regulating arachidonate metabolism were supported by the finding that pre-treatment of cells with PD098059 (an inhibitor of mitogen-activated protein kinase kinase-1 activation) reduced PDGF-stimulated cAMP synthesis. The cAMP formed in response to the arachidonate metabolites subsequently reduced the PDGF-dependent activation of c-Raf, MAPK, and DNA synthesis, suggesting the presence of a negative feedback pathway.",
keywords = "animals, arachidonic acid, calcium-calmodulin-dependent protein kinases, cells, cultured, cyclic AMP, cytosolic, DNA, guinea pigs, Muscle, Smooth, phospholipases A, phospholipases A2, platelet-derived growth factor, prostaglandin-endoperoxide synthases",
author = "Pyne, {N J} and S Pyne",
year = "1998",
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T1 - PDGF-stimulated cyclic AMP formation in airway smooth muscle

T2 - Cellular Signalling

AU - Pyne, N J

AU - Pyne, S

PY - 1998/5

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N2 - Platelet-derived growth factor (PDGF) stimulates cyclic AMP (cAMP) synthesis in cultured guinea-pig airway smooth muscle (ASM) cells. However, this stimulation is normally countered by the action of cAMP phosphodiesterases. Thus, cAMP synthesis was observed only in cells pre-treated with either 3-isobutyl-1-methylxanthine (IBMX) or with cholera toxin. cAMP synthesis was inhibited by pre-treating cells with well-defined inhibitors of arachidonate metabolite synthesis, such as AACOCF3 [a cytosolic phospholipase A2 (cPLA2) inhibitor] and indomethacin (a cyclooxygenase inhibitor). This suggests that arachidonate metabolites (e.g., prostaglandins) released in response to PDGF stimulate cAMP synthesis. The presence of functional prostaglandin (PG) receptors was confirmed by experiments that showed that exogenous PGE2 stimulated cAMP formation. cPLA2 is regulated by mitogen-activated protein kinase (MAPK) in a number of cell types. The presence of this pathway in ASM cells and its role in regulating arachidonate metabolism were supported by the finding that pre-treatment of cells with PD098059 (an inhibitor of mitogen-activated protein kinase kinase-1 activation) reduced PDGF-stimulated cAMP synthesis. The cAMP formed in response to the arachidonate metabolites subsequently reduced the PDGF-dependent activation of c-Raf, MAPK, and DNA synthesis, suggesting the presence of a negative feedback pathway.

AB - Platelet-derived growth factor (PDGF) stimulates cyclic AMP (cAMP) synthesis in cultured guinea-pig airway smooth muscle (ASM) cells. However, this stimulation is normally countered by the action of cAMP phosphodiesterases. Thus, cAMP synthesis was observed only in cells pre-treated with either 3-isobutyl-1-methylxanthine (IBMX) or with cholera toxin. cAMP synthesis was inhibited by pre-treating cells with well-defined inhibitors of arachidonate metabolite synthesis, such as AACOCF3 [a cytosolic phospholipase A2 (cPLA2) inhibitor] and indomethacin (a cyclooxygenase inhibitor). This suggests that arachidonate metabolites (e.g., prostaglandins) released in response to PDGF stimulate cAMP synthesis. The presence of functional prostaglandin (PG) receptors was confirmed by experiments that showed that exogenous PGE2 stimulated cAMP formation. cPLA2 is regulated by mitogen-activated protein kinase (MAPK) in a number of cell types. The presence of this pathway in ASM cells and its role in regulating arachidonate metabolism were supported by the finding that pre-treatment of cells with PD098059 (an inhibitor of mitogen-activated protein kinase kinase-1 activation) reduced PDGF-stimulated cAMP synthesis. The cAMP formed in response to the arachidonate metabolites subsequently reduced the PDGF-dependent activation of c-Raf, MAPK, and DNA synthesis, suggesting the presence of a negative feedback pathway.

KW - animals

KW - arachidonic acid

KW - calcium-calmodulin-dependent protein kinases

KW - cells, cultured

KW - cyclic AMP

KW - cytosolic

KW - DNA

KW - guinea pigs

KW - Muscle, Smooth

KW - phospholipases A

KW - phospholipases A2

KW - platelet-derived growth factor

KW - prostaglandin-endoperoxide synthases

U2 - 10.1016/S0898-6568(97)00138-1

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