Aggregation, Sorting and Transport of Chromogranins in the Regulated Secretory Pathway

Chromogranin A (CgA) and chromogranin B (CgB) belong to the granin family of acidic secretory proteins with widespread distribution in neuroendocrine tissue. They are co-packaged with other proneuropeptides and prohormones into exocytotic carriers, the secretory granules, and are processed to signalling molecules in this storage organelle. The analysis of the sorting of CgB revealed two key domains involved in sorting to the regulated secretory pathway. These domains are also conserved in CgA. One is an acidic domain inducing Ca2+ / pH-dependent aggregate formation in the trans-Golgi network. The other is a N-terminal loop structure, which is sufficient to direct secretory cargo to secretory granules. Furthermore, it appears that lipid micro-domains play an important role in cargo-membrane interaction. Recently, green fluorescent protein (GFP)-based imaging, employing fusion proteins of CgB and other regulated secretory proteins, has provided new insights into the dynamic complexity of the transport of secretory granules from the TGN to the F-actin-rich cortex. The resolution of this transport in time and space in conjunction with biochemical analyses led to the identification of motor proteins and cytoskeletal elements, which are part of the underlying molecular machinery. This knowledge greatly facilitated the interpretation of physiological studies on the regulated exocytosis of neuropeptides and hormones at the molecular level.