Insulin induces a selective heterologous desensitization of the mitogenic response of Swiss 3T3 cells to vasopressin

Abstract Prior incubation of confluent, quiescent cultures of Swiss 3T3 cells with insulin leads to a selective loss of mitogenic stimulation on re-addition of the combination of vasopressin and insulin in serum-free medium. The desensitization is specific for the action of vasopressin as insulin is fully active in the refractory cells when added in combination with other mitogens, whereas vasopressin is not. A prolonged treatment with insulin is required for induction of the refractoriness, half-maximal loss of response occurs after about 7 h and desensitization is complete after 12 h treatment. The refractory cells recover their response to vasopressin after more than 24 h incubation in the absence of insulin. A rapid response of the cells to vasopressin, inhibition of 125 I-epidermal growth factor ( 125 I-EGF) binding, is also desensitized by insulin. Desensitization is induced by insulin-like growth factor I (IGF-I), and partially by desoctapeptide insulin, but not by insulin B chain. Although the characteristics of insulin-induced desensitization are very similar to those of the homologous desensitization induced by vasopressin treatment, insulin does not bind to vasopressin antiserum or the [ 3 H]vasopressin receptors of Swiss 3T3 cells. Insulin treatment also does not lead to any down-regulation of [ 3 H]vasopressin receptors, and the refractoriness of the cells must therefore lie at a post-receptor step. Both insulin- and vasopressin-induced refractoriness to the mitogenic action of vasopressin can be blocked by a low level of cycloheximide. Both these agents therefore seem to induce the synthesis of specific protein(s) which selectively inhibit the mitogenic response of the cell to vasopressin.