Clinical Neuroendocrinology and Neuroendocrine Tumors

Transient Receptor Potential Channel TRPM8 Agonists Stimulate Calcium Influx and Neurotensin Secretion in Neuroendocrine Tumor Cells
Stefan Mergler^a, Mathias Z. Strowski^a, Simone Kaiser^c, Thomas Plath^c, Yvonne Giesecke^a, Marleen Neumann^a, Hiroshi Hosokawa^d, Shigeo Kobayashi^d, Jan Langrehr^b, Peter Neuhaus^b, Ursula Plöckinger^a, Bertram Wiedenmann^a, Carsten Grötzinger<sup>a

a</sup>Department of Internal Medicine, Division of Hepatology and Gastroenterology,
^bDepartment of Surgery, Charité - Universitätsmedizin Berlin, Campus Virchow Klinikum, and
^cmetaGen GmbH, Berlin, Germany;
^dDivision of Biological Information, Department of Intelligence Science and Technology, Graduate School of Informatics, Kyoto University, Kyoto, Japan

Address of Corresponding Author

Neuroendocrinology 2007;85:81-92 (DOI: 10.1159/000101693)

  Key Words

• TRPM8 channels
• Icilin
• Calcium
• Neurosecretory system
• Neurotensin

  Abstract

TRPM8 is a member of the melastatin-type transient receptor potential ion channel family. Activation by cold or by agonists (menthol, icilin) induces a transient rise in intracellular free calcium concentration ([Ca²⁺]_i). Our previous study demonstrated that Ca²⁺-permeable cation channels play a role in IGF-1-induced secretion of chromogranin A in human neuroendocrine tumor (NET) cell line BON [Mergler et al.: Neuroendocrinology 2006;82:87-102]. Here, we extend our earlier study by investigating the expression of TRPM8 and characterizing its impact on [Ca²⁺]_i and the secretion of neurotensin (NT). We identified TRPM8 expression in NET BON cells by RT-PCR, Western blotting and immunofluorescence staining. Icilin increased [Ca²⁺]_i in TRPM8-transfected human embryonic kidney cells (HEK293) but not in mock-transfected cells. Icilin and menthol induced Ca²⁺ transients in BON cells as well as in primary NET cell cultures of two different pancreatic NETs as detected by single cell fluorescence imaging. Icilin increased non-selective cation channel currents in BON cells as detected by patch-clamp recordings. This activation was associated with increased NT secretion. Taken together, this study demonstrates for the first time the expression TRPM8 in NET cells and its role in regulating [Ca²⁺]_i and NT secretion. The regulation of NT secretion in NETs by TRPM8 may have a potential clinical implication in diagnosis or therapy.

Copyright © 2007 S. Karger AG, Basel

  Author Contacts

Stefan Mergler
Department of Internal Medicine, Division of Hepatology and Gastroenterology
Charité - Universitätsmedizin Berlin, Campus Virchow Klinikum
Augustenburger Platz 1, DE-13353 Berlin (Germany)
Tel. +49 30 450 559 648, Fax +49 30 450 559 948, E-Mail stefan.mergler@charite.de

  Article Information

Received: December 15, 2006
Accepted after revision: February 22, 2007
Published online: April 5, 2007
Number of Print Pages : 12
Number of Figures : 6, Number of Tables : 0, Number of References : 68