Receptor-mediated targeting of hormones to secretory granules: role of carboxypeptidase E.

Peptide hormones, neuropeptides, and other molecules such as the granins are specifically packaged into granules of the regulated secretory pathway and released in a calcium-dependent manner upon stimulation. Many of these molecules are synthesized as larger precursors (prohormones) that are processed to biologically active products within the granules. It has now become apparent that prohormones, proneuropeptides, and the granins contain conformation-dependent sorting signal motifs that facilitate their specific sorting and packaging into regulated secretory granules. Recently, a receptor to which these sorting signals bind has been identified as the membrane form of carboxypeptidase E (CPE) and localized to the Golgi apparatus, where sorting occurs, specifically at the trans-Golgi network. In this article, we review the evidence for a sorting signal-receptor-mediated mechanism for routing peptide hormones and prohormones to the regulated secretory granules. We also describe a mouse model, Cpe(fat), which has the CPE gene naturally mutated. Pituitary hormones were misrouted and secreted in an unregulated manner via the constitutive pathway in these Cpe(fat) mice, leading to endocrine disorders.