FUNCTIONAL REGULATION OF GTP-BINDING PROTEIN COUPLED TO INSULIN-LIKE GROWTH FACTOR-I RECEPTOR BY LITHIUM DURING G(1) PHASE OF THE RAT-THYROID CELL-CYCLE

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-gamma-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-gamma-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-gamma-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 Ca2+ 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(l) phase of the FRTL-5 cell cycle.