Stimulation of Fc(alpha) receptors induces tyrosine phosphorylation of phospholipase C-gamma(1), phosphatidylinositol phosphate hydrolysis, and Ca2+ mobilization in rat and human mesangial cells.
Although knowledge of IgA Fc receptor (Fc(alpha)R) structure and gene organization has progressed in the past few years, signal transduction pathways elicited by its activation have hardly been studied. Previously, we have demonstrated that mesangial cells (MC) possess Fc(alpha)R stimulation triggers several biologic responses. In this work, we studied the early biochemical signals triggered by Fc(alpha)R stimulation in MC. MC incubation with aggregated IgA (AIgA) elicited a dose-dependent increase in cytosolic Ca2+ ([Ca2+]i). The response was rapid and transient, and slowly fell to the original baseline. Ca2+ mobilization was dependent on the Fc region of the IgA, because Fc, but neither Fab fragment nor carbohydrates, inhibited the [Ca2+] rise. The initial induction of [Ca2+]i rise was due to Ca2+ mobilization from inositol trisphosphate (IP3)-sensitive intracellular stores, while sustained levels were maintained through extracellular Ca2+ influx. Stimulation of Fc(alpha)R also resulted in production of IP3, temporally correlated with Ca2+ mobilization. Protein tyrosine kinase inhibitors abolished [Ca2+]i rise, indicating that tyrosine phosphorylation of some substrates is required for Ca2+ mobilization. Stimulation through Fc(alpha)R gave rise to a marked increase in tyrosine phosphorylation of several proteins, including the 147-kDa band, similar in size to phospholipase C-gamma(1) (PLC-gamma(1)). Tyrosine phosphorylation of PLC-gamma(1) reached a maximum 30 s after stimulation, as determined by immunoprecipitation and Western blot. Collectively, these results indicate that the Fc(alpha)R signaling pathway in MC involves PLC-(gamma(1) activation, IP3 formation, and Ca2+ mobilization, and is linked to activation of tyrosine kinases.
Gómez-Guerrero
C
C
Renal Research Laboratory, Jiménez Díaz Foundation, Autónoma University, Madrid, Spain.
Duque
N
N
Egido
J
J
D000818:Animals; D015703:Antigens, CD / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism*; D002478:Cells, Cultured; D019204:GTP-Binding Proteins / Q000378:metabolism; D005920:Glomerular Mesangium / Q000166:cytology / Q000276:immunology* / Q000378:metabolism*; D006801:Humans; D006868:Hydrolysis; D007070:Immunoglobulin A / Q000378:metabolism / Q000494:pharmacology; D007527:Isoenzymes / Q000378:metabolism*; D018129:Phosphatidylinositol Phosphates / Q000378:metabolism*; D051966:Phospholipase C gamma; D010766:Phosphorylation; D051381:Rats; D011961:Receptors, Fc / Q000378:metabolism*; D010738:Type C Phospholipases / Q000378:metabolism*; D014443:Tyrosine / Q000378:metabolism; D010566:Virulence Factors, Bordetella / Q000494:pharmacology
D015703:Antigens, CD; C036832:Fc(alpha) receptor; D007070:Immunoglobulin A; D007527:Isoenzymes; D018129:Phosphatidylinositol Phosphates; D011961:Receptors, Fc; D010566:Virulence Factors, Bordetella; D014443:Tyrosine; D010738:Type C Phospholipases; D051966:Phospholipase C gamma; D019204:GTP-Binding Proteins; D002118:Calcium