In thyroid cells, thyrotropin (TSH) is able to activate the phosphatidylinositol 4, 5-biphosphate (PIP2) as well as cAMP cascades, whereas thyroid stimulating antibody (TSAb) stimulates only adenylyl cyclase. Recently, it has been reported that TSAb can also activate PIP2 cascade in thyroid cells, but it seems that such TSAb may be restricted. To investigate whether most TSAb can activate PIP2 cascadeand what are the characteristics of TSAb to stimulate it, if restricted, we studied 28 patients with Graves' disease. In FRTL-5 cells, TSH activated both cAMP and PIP2 cascades and TSAb activated also cAMP phthway but most of them except noe did not stimulate it, if restricted, we studied 28 patients with Graves' disease. In FRTL-5 cells, TSH activated both cAMP and PIP2 cascades and TSAb activated also cAMP pathway but most of them except one did not stimulate PIP2 hydrolysis. Only one TSAb stimulated total inositol phosphates(IP) production in FRTL-5 cells and Cos-7 cells expressing the Mc2 and Mc4 mutant cDNA, values being 1.9, 2.1, 1.7 fold-increase over control, respectively. Moreover, the addition of phenylisopropyl adenosine (PIA) increased total IP production up to 3.3 fold-increase over control in this case. A Graes' patient with increase of total IP formation had high TBII activites (over 90%) after radioactive iodine treatment and pretibial myxedema but the degrees of goier size and hyperthyroidism were not severe. The blocking-type TSH receptor antibodies from patients with atrophic thyroiditis inhibited TSH-or TSAb-induced total IP as well as cAMP increase regardless of the addition of PIA, but had no effect on ATP-stimulated total IP production. These findings suggest that the TSAb to activate PIP2 cascade may be restricted and its pathway is activated by binding to TSH receptor(J Kor Soc Endocrinol 8: 422~431, 1993).