title: Roles of atypical protein kinase C in lysophosphatidic acid-induced type II adenylyl cyclase activation in RAW 264.7 macrophages.
abstract: 1 Lysophosphatidic acid (LPA) has been widely studied as a naturally occurring and multifunctional phospholipid messenger in diverse tissue and cell types and shown to inhibit adenylyl cyclase (AC) by a G protein-mediated mechanism. 2 In type II AC-expressing mouse RAW 264.7 macrophages, we showed that LPA at 3-50 microM increased cyclic AMP formation in a concentration-dependent manner, the effect being additive with that of forskolin or cholera toxin, and synergistic with that of prostaglandin E1 (PGE1) or isoproterenol. 3 The potentiation effect of LPA was unaffected by the removal of serum or pertussis toxin treatment. 4 Both colchicine and cytochalasin B potentiated the cyclic AMP response to PGE1, the effect being additive to that of LPA. 5 On studying the regulation of type II AC by protein kinase C (PKC), phorbol 12-myristate-13 acetate (PMA) potentiated the PGE1-elicited cyclic AMP response, this effect being non-additive to that of LPA, suggesting that PKC activation was the common mechanism involved in AC potentiation by LPA and PMA. 6 PKC inhibitor Ro 31-8220, but not Go 6976, significantly inhibited the LPA-induced cyclic AMP potentiation. 7 The potentiation effect of LPA was unaffected by long-term treatment with PMA, which resulted in the down-regulation of PKCalpha, betaI, betaII and PKCdelta, but not PKCepsilon, mu, lambda and zeta. 8 By in situ kinase assay, we found a marked increase in atypical PKC activity after LPA treatment. 9 Taken together, we conclude that LPA can elicit a unique signalling cascade in RAW 264.7 macrophages and increase type II AC activity via the activation of atypical PKC.
authors.affiliation: Department of Pharmacology, College of Medicine, National Taiwan University, Taipei, Taiwan. wwl@ha.mc.ntu.edu.tw
authors.forename: W W
authors.initials: WW
authors.lastname: Lin
authors.forename: S H
authors.initials: SH
authors.lastname: Chang
authors.forename: S M
authors.initials: SM
authors.lastname: Wang
mesh_terms: D037361:Adenylate Cyclase Toxin; D000262:Adenylyl Cyclases / Q000378:metabolism*; D000527:Alprostadil / Q000494:pharmacology; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D002772:Cholera Toxin / Q000494:pharmacology; D003078:Colchicine / Q000494:pharmacology; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism; D003571:Cytochalasin B / Q000494:pharmacology; D003599:Cytoskeleton / Q000187:drug effects / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects; D019204:GTP-Binding Proteins / Q000378:metabolism; D007211:Indoles / Q000494:pharmacology; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000378:metabolism; D007545:Isoproterenol / Q000494:pharmacology; D008244:Lysophosphatidylcholines / Q000494:pharmacology; D008246:Lysophospholipids / Q000494:pharmacology*; D008264:Macrophages / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology; D037342:Pertussis Toxin; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology*; D019311:Staurosporine / Q000494:pharmacology; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D010566:Virulence Factors, Bordetella / Q000494:pharmacology
chemical_list: D037361:Adenylate Cyclase Toxin; D007211:Indoles; D007527:Isoenzymes; D008244:Lysophosphatidylcholines; D008246:Lysophospholipids; D010566:Virulence Factors, Bordetella; D005576:Colforsin; D003571:Cytochalasin B; D002772:Cholera Toxin; D000242:Cyclic AMP; D037342:Pertussis Toxin; D011493:Protein Kinase C; D019204:GTP-Binding Proteins; D000262:Adenylyl Cyclases; C100622:adenylyl cyclase 2; D000527:Alprostadil; D019311:Staurosporine; D007545:Isoproterenol; D013755:Tetradecanoylphorbol Acetate; D003078:Colchicine; D002118:Calcium; C064758:Ro 31-8220