The Interactions of Proinsulin with Insulin Receptors on the Plasma Membrane of the Liver

Pierre Freychet

doi:10.1172/JCI107845

The Interactions of Proinsulin with Insulin Receptors on the Plasma Membrane of the Liver

Pierre Freychet

Published November 1, 1974 - More info

View PDF

Abstract

The interactions of proinsulin with the insulin-specific receptors were investigated in purified rat liver plasma membranes. These studies were designed to characterize the binding of proinsulin to the insulin receptors, to search for proinsulin-specific receptor sites, and to examine the possibility of proinsulin conversion at the insulin receptor site. Proinsulin was only 3-5% as potent as insulin in binding to insulin receptors. Proinsulin reacted with all of the insulin-specific receptors, and direct binding studies of [¹²⁵I]porcine proinsulin and [¹²⁵I]rat proinsulin did not reveal proinsulin-specific receptor sites other than the insulin receptors in rat liver membranes.

Quantitative data derived from steady-state and transient-state comparative binding studies of both [¹²⁵I]proinsulin and [¹²⁵I]insulin indicated that a 20-fold lower association rate constant essentially accounts for the reduced affinity of proinsulin for the insulin receptors. The possibility of proinsulin conversion at the insulin receptor sites was investigated. Material recovered from the membranes upon dissociation of the proinsulin-receptor complex was intact proinsulin and did not exhibit any conversion by a variety of analytical methods.

These results indicate that the lower affinity of proinsulin for the insulin receptor in the liver is an intrinsic property of the proinsulin molecule. The lower uptake of proinsulin by the insulin receptor represents, in addition to a slower degradation of the prohormone, a further mechanism by which proinsulin exerts prolonged, albeit reduced, action in vivo.