title: Mechanisms of the lysophosphatidic acid-induced increase in [Ca(2+)](i) in skeletal muscle cells.
abstract: Although lysophosphatidic acid (LPA) is known to increase intracellularfree calcium concentration ([Ca(2+)](i)) in different cell types, the effect of LPA on the skeletal muscle cells is not known. The present study was therefore undertaken to examine the effect of LPA on the [Ca(2+)](i) in C2C12 cells. LPA induced a concentration and time dependent increase in [Ca(2+)](i), which was inhibited by VPC12249, VPC 32183 and dioctanoyl glycerol pyrophosphate, LPA1/3 receptor antagonists. Pertussis toxin, a G(i) protein inhibitor, also inhibited the LPA-induced increase in [Ca(2+)](i). Inhibition of tyrosine kinase activities with tyrphostin A9 and genistein also prevented the increase in [Ca(2+)](i) due to LPA. Likewise, wortmannin and LY 294002, phosphatidylinositol 3-kinase (PI3-K) inhibitors, inhibited [Ca(2+)](i) response to LPA. The LPA effect was also attenuated by ethylene glycolbis(beta-aminoethylether)-N,N,N',N'-tetraacetic acid (EGTA), an extracellular Ca(2+) chelator, Ni(2+) and KB-R7943, inhibitors of the Na(+)-Ca(2+) exchanger; the receptor operated Ca(2+) channel (ROC) blockers, 2-aminoethoxydiphenyl borate and SK&F 96365. However, the L-type Ca(2+) channel blockers, verapamil and diltiazem; the store operated Ca(2+) channel blockers, La(3+) and Gd(3+); a sarcoplasmic reticulum calcium pump inhibitor, thapsigargin; an inositol trisphosphate receptor antagonist, xestospongin and a phospholipase C inhibitor, U73122, did not prevent the increase [Ca(2+)](i) due to LPA. Our data suggest that the LPA-induced increase in [Ca(2+)](i) might occur through G(i)-protein coupled LPA(1/3) receptors that may be linked to tyrosine kinase and PI3-K, and may also involve the Na(+)-Ca(2+) exchanger as well as the ROC. In addition, LPA stimulated C2C12 cell proliferation via PI3-K. Thus, LPA may be an important phospholipid in the regulation of [Ca(2+)](i) and growth of skeletal muscle cells.
authors.affiliation: Institute of Cardiovascular Sciences, St. Boniface Hospital Research Centre, Winnipeg, Manitoba, Canada.
authors.forename: Yan-Jun
authors.initials: YJ
authors.lastname: Xu
authors.forename: Paramjit S
authors.initials: PS
authors.lastname: Tappia
authors.forename: Ramesh K
authors.initials: RK
authors.lastname: Goyal
authors.forename: Naranjan S
authors.initials: NS
authors.lastname: Dhalla
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism*; D015220:Calcium Channels / Q000378:metabolism; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D019204:GTP-Binding Proteins / Q000378:metabolism; D007424:Intracellular Fluid / Q000378:metabolism*; D008246:Lysophospholipids / Q000494:pharmacology*; D051379:Mice; D008954:Models, Biological; D018482:Muscle, Skeletal / Q000166:cytology / Q000187:drug effects* / Q000254:growth & development; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D049368:Receptors, Lysophosphatidic Acid / Q000378:metabolism; D019831:Sodium-Calcium Exchanger / Q000378:metabolism; D013997:Time Factors
chemical_list: D015220:Calcium Channels; D008246:Lysophospholipids; D049368:Receptors, Lysophosphatidic Acid; D019831:Sodium-Calcium Exchanger; D019869:Phosphatidylinositol 3-Kinases; D011505:Protein-Tyrosine Kinases; D019204:GTP-Binding Proteins; C032881:lysophosphatidic acid; D002118:Calcium