highlights 2008

Differential expression of the regulated catecholamine secretory pathway in different hereditary forms of pheochromocytoma

Pheochromocytomas in patients with von Hippel-Lindau (VHL) syndrome and multiple endocrine neoplasia type 2 (MEN 2) differ in the types and amounts of catecholamines produced and the resulting signs and symptoms. We hypothesized the presence of different processes of catecholamine release reflecting differential expression of components of the regulated secretory pathway amongst the two types of hereditary tumors. Differences in catecholamine secretion from tumors in patients with VHL syndrome (n=47) and MEN 2 (n=32) were examined using measurements of catecholamines in tumor tissue, urine and plasma, the latter under baseline conditions in all subjects and in a subgroup of patients who received intravenous glucagon to provoke catecholamine release. Microarray and proteomics analyses, quantitative PCR, and Western blotting were used to assess expression of tumor tissue secretory pathway components. The rate constant for baseline catecholamine secretion was 20-fold higher in VHL than in MEN 2 tumors (0.359±0.094 versus 0.018±0.009 day-1), but catecholamine release was only responsive to glucagon in MEN 2 tumors. Compared to tumors from MEN 2 patients, those from VHL patients were characterized by reduced expression of numerous components of the regulated secretory pathway (e.g., SNAP25, syntaxin, rabphilin 3A, annexin A7, calcium-dependent secretion activator). The mutation-dependent differences in expression of secretory pathway components indicate a more mature regulated secretory pathway in MEN 2 than VHL tumors. These data provide a unique mechanistic link to explain how variations in the molecular machinery governing exocytosis may contribute to clinical differences in the secretion of neurotransmitters or hormones and the subsequent presentation of a disease.



Figure Legend. Schematic model illustrating constitutive versus regulated secretory pathways (A) with insets B and C indicating magnifications of secretory granules to illustrate the catecholamine biosynthetic pathway (B) and the catecholamine regulated secretory pathway (C). For most definitions of abbreviations see Table 2. Other abbreviations: TYR, tyrosine; DOPA, dihydroxyphenylalanine; DA, dopamine; NE, norepinephrine; EPI, epinephrine; AADC, aromatic amino acid decarboxylase; NET, norepinephrine transporter.

Published in Am J Physiol Endocrinol Metab. 2008 Oct 14 PMID: 18854424