To gain insight into the mechanisms responsible for the impaired glycogenolytic response to glucagon and the diminished ketogenic capacity of newborn guinea pig, we studied the ontogeny of insulin and glucagon receptors, and the responsiveness of the adenylate cyclase complex to glucagon, PGE1NaF, and cholera toxin in liver plasma membrane from fetal (58 d, late gestation, and 65 d, term) and adult guinea pigs. The number of insulin receptors (7×10-1M/L) was least in 58-d fetus (3.0 ± 0.4; mean ± SEM) and increased 3-fold in 65 d fetus (8.8 ± 0.6; P < 0.01). In adult guinea pig, both insulin receptor number (6.0 ± 0.7) and average affinity constant (1.20 ± 0.08 × 108M-1) were significantly lower (P < 0.01) compared with 65-d fetus. The number of glucagon receptors remained unchanged between 58-d and 65-d fetuses, but both average and high affinity association constants were significantly higher at d 65. In contrast to the lower capacity and affinity of insulin receptors in the adult compared with term fetus, the total glucagon receptor number (×10-10M/L) in adults (7.2 ± 0.8) was twice that of the 58 d (3.2 ± 0.2) and 65 d (3.2 ± 1.0) fetuses. The average affinity constant (×108M-1) in adult (3.8 ± 0.2) was, however, significantly lower than the two fetal groups (58 d, 5.0 ± 0.3; P < 0.05 and 65 d, 8.1 ± 1.0; P < 0.05). Although the total glucagon receptor number at d 58 was approximately 50% of that present in the adult, glucagon did not stimulate cAMP production above basal; all other stimuli evoked significant increases. By 65 d, the fetal membranes responded to glucagon as well as to all other agents with appropriate cAMP production. In the presence of 0.5 mM guanosine-5'-triphosphate, the cAMP response to prostaglandin El was similar in all three groups. These results demonstrate the following in liver plasma membrane from the guinea pig. 1) At term, insulin receptor numbers are higher than in less mature fetus or in adult. 2) There is a delay in maturation of functional glucagon receptors coupled to the adenylate cyclase complex. 3) Apart from failure of response to glucagon, the adenylate cyclase complex is otherwise functionally mature even at 58 d because it responds to PGE, and other agents.