We analyse the role of the G proteins in regulating collagen gene expression by measuring collagen alpha 1(I) mRNA levels in cultured hepatic stellate cells in basal conditions and after stimulating or inhibiting the major intracellular signalling pathways. Stimulation of Gs protein and adenylyl cyclase or the addition of 8Br-cAMP to the cells led to a decrease in collagen alpha 1(I) mRNA levels, while blocking protein kinase A abolished this effect. Blocking Gi protein, phospholipase A2 and C, calcium channels and calmodulin resulted in a significant increase in collagen mRNA levels. PKC stimulation led to a marked decrease in these levels. These results suggest that collagen gene expression is inhibited by a number of intracellular pathways. A Gs and a pertussis toxin-sensitive G protein seem to initiate cellular response. Transcription factors, acting in these pathways, must be identified. However, it seems that they do not need to be synthesised.