Autoanti-phosphatidylinositide antibodies specifically inhibit noradrenaline effects on Ca2+ and Cl- channels in rat portal vein myocytes.
High levels of circulating autoantibodies (auto-Ab) directed against phosphatidylinositides have been identified in the sera of patients with malignant tumors. These polyclonal autoantibodies had higher avidity and specificity for phosphatidylinositol (PtdIns) than for the other phosphatidylinositides. Effects of the auto-Ab were studied in smooth muscle myocytes in the PtdIns-involving transduction mechanism triggered by activation of alpha 1-adrenoceptors. Noradrenaline activated a Ca(2+)-dependent Cl- current through the Ca(2+)-releasing action of inositol 1,4,5-trisphosphate (InsP3) and enhanced the Ca2+ channel current through a diacylglycerol and protein kinase C-dependent mechanism. External applications of auto-Ab (0.03-0.3 mg/ml) were without effect on noradrenaline-induced responses whereas intracellular applications (0.0004-0.012 mg/ml) inhibited both Cl- current activation and Ca2+ channel current stimulation. Intracellular applications of IgG from healthy donors had no effect on noradrenaline-induced responses. When anti-PtdIns Ab were preincubated with PtdIns the inhibition of the noradrenaline-induced responses on Ca2+ and Cl- channels was not observed. Autoanti-PtdIns Ab inhibited also the acetylcholine-activated Cl- current, confirming that the acetylcholine response was mediated through the phosphatidylinositol breakdown. In contrast, the autoanti-PtdIns Ab were ineffective against the transduction pathway after beta-adrenoceptor activation. Therefore, these results suggest that the biological effect of autoanti-PtdIns Ab results from a specific binding to membrane PtdIns or PtdIns metabolites and thereby prevented InsP3 and diacylglycerol production. These autoanti-PtdIns Ab appear to be a new specific tool to identify the role of phosphatidylinositides in intracellular transduction processes.
Loirand
G
G
Laboratoire de Physiologie Cellulaire et Pharmacologie Moléculaire, Institut National de la Santé et de la Recherche Médicale CJF 88-13, Université de Bordeaux II, France.
Faiderbe
S
S
Baron
A
A
Geffard
M
M
Mironneau
J
J
D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D001323:Autoantibodies / Q000276:immunology*; D002110:Caffeine / Q000494:pharmacology; D015220:Calcium Channels / Q000378:metabolism* / Q000502:physiology; D018118:Chloride Channels; D004075:Diglycerides / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D015544:Inositol 1,4,5-Trisphosphate / Q000378:metabolism; D008564:Membrane Potentials / Q000187:drug effects; D008565:Membrane Proteins / Q000378:metabolism* / Q000502:physiology; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000378:metabolism* / Q000502:physiology; D009638:Norepinephrine / Q000037:antagonists & inhibitors*; D010716:Phosphatidylinositols / Q000276:immunology*; D011169:Portal Vein / Q000166:cytology / Q000378:metabolism*; D011493:Protein Kinase C / Q000378:metabolism; D051381:Rats; D011942:Receptors, Adrenergic, alpha / Q000378:metabolism; D015398:Signal Transduction
D001323:Autoantibodies; D015220:Calcium Channels; D018118:Chloride Channels; D004075:Diglycerides; D008565:Membrane Proteins; D010716:Phosphatidylinositols; D011942:Receptors, Adrenergic, alpha; D002110:Caffeine; D015544:Inositol 1,4,5-Trisphosphate; D011493:Protein Kinase C; D000109:Acetylcholine; D009638:Norepinephrine