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The orientation of insulin receptors in the red cell membrane

High‐affinity binding of insulin to receptors in human erythrocyte membranes occurred at the external surface, but not at the cytoplasmic surface of the plasma membrane, as assessed by insulin binding to right‐side‐out and inside‐out membrane vesicles. Even after prolonged (3 h) incubation at 22°C, binding at the cytoplasmic membrane aspect remained negligible. The data indicate that the insulin receptor displays its hormone‐binding site exclusively toward the extracellular space and that transmembrane mobility (“flip‐flop”) of the receptor from one to the other membrane leaflet is severely restricted.