Figure 1. Overview of the secretory pathway. The trans-Golgi network (TGN) is the cellular compartment where the different proteins start the sorting process that will finally result in secretion. Lysosomal enzymes (squares) bind to mannose-6-phosphate receptors (–[) that direct targeting to the lysosomes. Regulated secretory proteins (small circles) begin to aggregate in the TGN and this may, in turn, trigger association of the proteins with membrane lipid rafts (small ellipses). This association directs packaging into immature secretory granules (ISG) which ultimately become the dense-core mature secretory granules (MSG) of the regulated secretory pathway. In this model, some proteins exit the TGN already sorted and packaged into transport vesicles, destined for the lysosomes or to be constitutively secreted, whereas other proteins enter the ISG only partially sorted. Refinement of the granule components and hence final sorting occurs at the ISG by removal of constitutively secreted proteins and lysosomal proteins during granule maturation. Regulated secretory proteins may be retained in the maturing granule due to their aggregation and association with the membrane. COP: coatomer protein.

Figure 2. Sorting via lipid rafts. Proteins to be secreted via the regulated secretory pathway (small circles and crosses) are initially sorted in the TGN. Owing to the acidic pH and the high Ca²⁺ concentration encountered in the TGN, proteins form aggregates that associate with specific microdomains in the membrane termed lipid rafts (small ellipses). This association can occur via association with other proteins that could be acting as a sorting receptor (triangles) and thus anchoring the aggregated proteins to the lipid rafts, or directly with the lipid components of the rafts. The nascent vesicle containing the proteins buds from the TGN to form the ISG, which after maturation and fusion with other granules results in the formation of an MSG whose contents will be secreted upon stimulation of the cell with a secretagogue.