Functional regulation of GTP‐binding protein coupled to insulin‐like growth factor‐I receptor by lithium during G1 phase of the rat thyroid cell cycle

Abstract The regulatory effects of lithium on the function of pertussis toxin-sensitive GTP-binding (G i )-proteins located on the mitogenic pathway activated by insulin-like growth factor-I (IGF-I) in FRTL-5 cells were studied. Addition of GTP-γ-S to the thyroid stimulating hormone-primed cell membranes resulted in a decreased affinity of IGF-I receptor binding, and the dissociation constant ( K d ) increased from 0.46 nM to 3.1 nM. Moreover, IGF-I stimulated GTP-γ-S binding to a 40-kDa protein, and pertussis toxin (PT) attenuated the stimulatory effect of IGF-I on the same protein. Lithium lowered the affinity of IGF-I receptor binding and the K d (3.4 nM) was in the same range as that in the presence of GTP-γ-S. The inhibitory effect of lithium was markedly abolished by pretreatment with PT. Lithium attenuated the amounts of ADP-rebosylation of the 40-kDa protein by PT. In addition, lithium stimulated Ca 2+ entry, similar to that by IGF-I, and induced cell proliferation via a PT-sensitive step. These findings suggest that lithium may be capable of modulating the function of G i -proteins coupled to IGF-I receptors during the G 1 phase of the FRTL-5 cell cycle.