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- Title
Insulin-Like Growth Factor-1 Increases Intracellular Calcium Concentration in Human Primary Neuroendocrine Pancreatic Tumor Cells and a Pancreatic Neuroendocrine Tumor Cell Line (BON-1) via R-Type Ca Channels and Regulates Chromogranin A Secretion in BON-1 Cells
- Authors
Mergler, Stefan; Strauss, Olaf; Strowski, Mathias; Prada, Javier; Drost, Adriana; Langrehr, Jan; Neuhaus, Peter; Wiedenmann, Bertram; Ploeckinger, Ursula
- Abstract
Insulin-like growth factor 1 (IGF-1) is a potent mitogenic and secretory factor that acts on voltage operated Ca2+ channels (VOCCs). VOCCs are categorized into L-type channels (CaV1.1–1.4), P/Q-type channels (CaV2.1), N-type channels (CaV2.2), R-type channels (CaV2.3), and T-type channels (CaV3.1–3.3). Aside from regulating membrane excitability, VOCCs influence chromogranin A (CgA) secretion in neuroendocrine tumor (NET) cells. It is not known, whether VOCCs play a role in the IGF-1-dependent regulation of CgA secretion in NET cells. We therefore studied the effects of IGF-1 on individual VOCC subtypes and characterized their role in mediating IGF-1-dependent regulation of CgA secretion in NET cells. Using specific modulators of VOCC subtypes, we identified the functional expression of L-, N-, P/Q- and R-type channels in primary as well as permanent models of NET. The IGF-1-induced intracellular Ca2+ increase in NET cells was mainly due to the activation of R-type channel activity. The effects on intracellular calcium, observed in whole-cell patch-clamp recordings and fluorescence imaging, were partially blocked by the specific R-type channel blocker SNX-482 and antisense oligonucleotides against the α1 subunit of this channel. IGF-1 potently induced CgA secretion. The effect of IGF-1 was reduced by both, inhibition of R-type channel activity and a reduction of R-type channel expression using antisense oligonucleotides. Since R-type channels exist in NET cells and couple to both, IGF-1 receptor signaling as well as CgA secretion, pharmacological interference with R-type channels may represent a new therapeutic option by blocking Ca2+ signaling thereby abrogating IGF-1-dependent hypersecretion in NET disease. Copyright © 2005 S. Karger AG, Basel
- Subjects
SOMATOMEDIN; CELLULAR control mechanisms; REGULATION of cell growth; GLANDS; BIOLOGICAL transport; NEUROENDOCRINE tumors; OLIGONUCLEOTIDES; HYPOGLYCEMIC agents
- Publication
Neuroendocrinology, 2005, Vol 82, Issue 2, p87
- ISSN
0028-3835
- Publication type
Article
- DOI
10.1159/000091008