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A more recent version of this article appeared on March 1, 2003
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Submitted on May 24, 2002
Revised on September 30, 2002
Accepted on November 6, 2002
-cells via the regulated pathway
1 Louis-Jeantet Research Laboratories, University Medical Center, 1211 Geneva 4, Switzerland
* Corresponding author. E-mail address: ronw{at}chw.edu.au.
Prohormones are directed from the trans-Golgi-network (TGN) to secretory granules of the regulated secretory pathway. It has further been proposed that prohormone conversion by endoproteolysis may be necessary for subsequent retention of peptides in granules and to prevent their release by the so-called "constitutive-like" pathway. To address this directly, mutant human proinsulin (Arg/Gly32:Lys/Thr64) that cannot be cleaved by conversion endoproteases, was expressed in primary rat islet cells by recombinant adenovirus. The handling of the mutant proinsulin was compared with that of wildtype human proinsulin. Infected islet cells were pulse-labeled and both basal and stimulated secretion of radiolabeled products followed during a chase. Labeled products were quantified by high performance liquid chromatography. As expected, the mutant proinsulin was not converted at any time. Basal (constitutive and "constitutive-like") secretion was higher for the mutant proinsulin than for wildtype proinsulin/insulin, but amounted to <1% even during a prolonged (6 h) period of basal chase. There was no difference in stimulated (regulated) secretion of mutant and wildtype proinsulin/insulin at any time. Thus, in primary islet cells, unprocessed (mutant) proinsulin is sorted to the regulated pathway and then retained in secretory granules as efficiently as fully processed insulin.
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