Chromogranins as regulators of exocytosis

Abstract

Chromogranins (Cgs) constitute the main protein component in the vesicular matrix of large dense core vesicles (LDCV). These acidic proteins have been implicated in several physiological processes such as vesicle sorting, the generation of bioactive peptides and the accumulation of soluble species inside LDCV. This latter feature of Cgs accounts for the ability of vesicles to concentrate catecholamines and Ca 2+. Indeed, the low affinity and high capacity of Cgs to bind solutes at the low pH of the LDCV lumen seems to be behind the delay in the neurotransmitter exit towards the extracellular milieu after vesicle fusion. The availability of new mouse strains lacking Cgs in combination with the arrival of several techniques for the direct monitoring of exocytosis (like amperometry, patchamperometry and intracellular electrochemistry), have helped advance our understanding of how these granins concentrate catecholamines and Ca 2+ in LDCV, and how they influence the kinetics of exocytosis. In this review, we will discuss the roles of Cgs A and B in maintaining the intravesicular environment of secretory vesicles and in exocytosis, bringing together the most recent findings from adrenal chromaffin cells.

Impact of Chromogranin A deficiency on catecholamine storage, catecholamine granule morphology and chromaffin cell energy metabolism in vivo

“…CgA binds catecholamines with low affinity (K d =2.1 × 10 −3 M) but high capacity (32 mol catecholamines/mol CgA) (Videen et al 1992) allowing it to form a binding complex within the vesicle (Berneis et al 1973; Kopell and Westhead 1982; Mahapatra et al 2004; Yoo and Albanesi 1991). A theoretical osmolarity of 1500 mOsm has been calculated for the internal volume of the DCV, from the concentrations of its constituents if these were not bound in an osmotically inert form (Borges et al 2010). By reducing the number of free molecules and ions within the solution, the binding of CgA with catecholamines and Ca 2+ provides a mechanism for reducing this theoretical intravesicular osmotic pressure, incompatible with vesicle integrity given its water permeability and facilitating the storage of high concentrations of the transmitter within the small volume of the vesicle (Haigh et al 1989; Kopell and Westhead 1982).…”

Chromogranins A and B are key proteins in amine accumulation, but the catecholamine secretory pathway is conserved without them

“…The lack of CgA promotes the overexpression of CgB and vice versa (26). Conversely, the absence of both granins did not significantly increase the expression of SgII (Supplemental Fig.…”

Chromogranin A as circulating marker for diagnosis and management of neuroendocrine neoplasms: more flaws than fame

“…Besides being stored into secretory vesicles, the members of the granin family have many common properties, such as a similar acidic isoelectric point, the capacity to bind calcium ions and the ability to form aggregates. Furthermore, their structure typically includes multiple dibasic cleavage sites, which allow the processing into smaller peptides, each displaying a differential function (O'Connor & Frigon 1984, Gerdes et al 1988, Borges et al 2010, Mahata et al 2010, SanchezMargalet et al 2010, Helle & Corti 2015. Human CgA is encoded by the CHGA gene, located on chromosome 14q32.12.…”

“…Based on the relationship with codified hormone-related syndromes, circulating markers of NEN are differentiated in common or broad spectrum, including chromogranin A (CgA), pancreatic polypeptide and neuron-specific enolase, and specific or individual, including serotonin and its metabolite 5-hydroxyindolylacetic acid, gastrin, glucagon, insulin, C-peptide, vasoactive intestinal peptide, somatostatin, histamine, calcitonin, parathyroid, somatotropic, adrenocorticotropic hormones, catecholamines and their metabolites and neuropeptides (Ferolla et al 2008). The present review is focused on CgA, a hydrophilic glycoprotein abundantly expressed in large dense core vesicles of neuroendocrine cells, whose main biological role is to regulate calcium-mediated exocytosis (Borges et al 2010). Consistent with the definition of a common marker, elevated levels of circulating CgA have been associated with almost all types of NEN, including those arising from the gastroenteropancreatic tract and the bronchopulmonary area, which represent the majority, but also pheocromocytomas/paragangliomas, medullary thyroid carcinoma, Merkel cell carcinoma of the skin and (even if data are controversial) pituitary and parathyroid adenomas (Sobol et al 1986, Blind et al 1992, Kimura et al 1997, Nobels et al 1997, Guignat et al 2001, Tomassetti et al 2001b, Campana et al 2007, Zatelli et al 2007).…”