Abstract:Cell surface binding, internalization, and biological effects of insulin‐like growth factors (IGFs) I and II have been studied in primary neuronal cultures from developing rat brain (embryonic day 15). Two types of IGF binding sites are present on the cell surface. The IGF‐I receptor α‐subunit (Mr125,000) binds IGF‐I with aKDof 1 nMand IGF‐II with 10 times lower affinity. The mannose‐6‐phosphate (Man‐6‐P)/IGF‐II receptor (Mr250,000) binds IGF‐II with aKDof 0.5 nMand IGF‐I with 100 times lower affinity. Surface‐bound IGF‐I and IGF‐II are internalized by their respective receptors and degraded to amino acids. Man‐6‐P increases the receptor binding and internalization of IGF‐II but not those of IGF‐I. Neuronal synthesis of RNA and DNA is increased twofold by IGF‐I with 10 times higher potency than IGF‐II. Antibody 3637, which blocks receptor binding of IGF‐II, has no effect on the DNA response to IGF‐I or IGF‐II. Double immunocytochemical staining with antibodies to bromodeoxyuridine and neurofilament shows that>80% of the bromodeoxyuridine‐positive cells become neurofilament positive. It is concluded that IGF‐I and IGF‐II bind to two receptors on the surface of neuronal precursor cells that mediate endocytosis and degradation of IGF‐I and IGF‐II. Proliferation of neuronal precursor cells is stimulate