18.13:
Overview of Secretory Vesicles
Eukaryotic cells secrete proteins both as a continuous process and in response to specific stimuli.
The continuous release, also called constitutive secretion, occurs without any specific stimulus. It is the default pathway that transports molecules to the plasma membrane, including extracellular matrix proteins, interleukins, and certain growth factors.
Constitutively secreted proteins are continuously transported to the plasma membrane and are sorted into unregulated secretory vesicles. In contrast, secretory proteins, such as insulin and neurotransmitters, are released upon stimulation and are transported in regulated secretory vesicles.
Newly synthesized secretory proteins are first loosely aggregated in immature secretory vesicles that bud off from the trans-Golgi network. During maturation, the vesicles fuse with each other.
As the vesicles fuse, the concentration of V-type ATPases present on the vesicular membrane also increases. The V-type ATPases pump protons into the vesicle, leading to a drop in the intraluminal pH of the vesicles.
This process forms mature secretory vesicles with concentrated protein aggregates. The concentration ensures the delivery of large amounts of protein to the cell surface.
18.13:
Overview of Secretory Vesicles
Secretory vesicles, also known as dense core vesicles (DCVs), are membrane-bound vesicles that transport secretory proteins, such as hormones or neurotransmitters. Regulated secretory vesicles transport proteins from the trans-Golgi network to the exterior of the cell. Proteins present in regulated secretory vesicles are required to be rapidly exocytosed in large amounts upon a specific stimulus.
Various proteins regulate the aggregation of molecules inside the secretory vesicles. Chromogranins (Cgs) A and B are proteins that bind to soluble molecules present in secretory vesicles. This binding aggregates the soluble molecules, forming DCVs. Cgs function optimally at low pH and high intracellular calcium concentration. The low pH is maintained by the continuous pumping of protons by the V-type ATPases. A high concentration of calcium is present in the endoplasmic reticulum and Golgi complex of most mammalian cells. Hence, the secretory vesicles that bud off from the trans-Golgi network are rich in calcium. Calcium induces pH-dependent conformational changes in Cgs A and B. These conformational changes lead to the binding and aggregation of CgsA and B among other vesicular matrix proteins with the vesicular membrane. Aggregation is important for specific proteins to be sorted into regulated secretory vesicles.
The yeast Saccharomyces cerevisiae is a model system for studying the regulation of secretory vesicle-mediated transport. In 1979, Randy Schekman and Peter Novik generated temperature-sensitive mutants of S. cerevisiae. These mutants expressed proteins that were functional only at low temperatures but not at 37°C. Schekman and Novik observed that these mutants accumulated vesicles and internal membranes. These mutants were also defective in different stages of protein secretion and therefore called them sec mutants. Some sec mutants contained vesicles that were unable to fuse with the plasma membrane, while other mutants could not transport proteins to other organelles. Further, molecular analysis of these mutants revealed 23 sec genes that produced proteins with regulatory roles in different transport stages of secretory vesicles.
Suggested Reading
- Yoo, S. H. (1996). pH-and Ca2+-dependent Aggregation Property of Secretory Vesicle Matrix Proteins and the Potential Role of Chromogranins A and B in Secretory Vesicle Biogenesis (∗). Journal of Biological Chemistry, 271(3), 1558-1565.
- Bond LM, Brandstaetter H, Sellers JR, Kendrick-Jones J, Buss F. Myosin motor proteins are involved in the final stages of the secretory pathways. Biochem Soc Trans. 2011;39(5):1115-1119. doi:10.1042/BST0391115
- Trexler, A. J., & Taraska, J. W. (2017). Regulation of insulin exocytosis by calcium-dependent protein kinase C in beta cells. Cell Calcium, 67, 1-10.
- Spang A. (2015). Anniversary of the discovery of sec mutants by Novick and Schekman. Molecular biology of the cell, 26(10), 1783–1785. https://doi.org/10.1091/mbc.E14-11-1511