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TRANSLATIONAL PHYSIOLOGY

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

¹Institute of Clinical Chemistry and Laboratory Medicine and ²Department of Medicine, University of Dresden, Dresden, Germany; ³Reproductive and Adult Endocrinology Program, National Institute of Child Health and Human Development; ⁴Genome Technology Branch, National Human Genome Research Institute; ⁵Metabolism Branch and ⁶Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute; ⁷Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda; ⁸Department of Chemistry and Biochemistry, University of Maryland, College Park, Maryland; ⁹Department of Clinical Pathophysiology, University of Florence, Florence, Italy; and ¹⁰Department of Internal Medicine, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands

Submitted 14 July 2008 ; accepted in final form 15 September 2008

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 among 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 last of which was 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 vs. 0.018 ± 0.009 day^–1), but catecholamine release was responsive only to glucagon in MEN 2 tumors. Compared with 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.

secretion; exocytosis; von Hippel-Lindau; multiple endocrine neoplasia type 2