Calcitonin gene-related peptide (CGRP) and calcitonin (CT) are secreted by medullary thyroid carcinoma (MTC). Relationships between extracellular calcium ([Ca2+](e)), cytosolic free calcium ([Ca2+](i)) (as measured with fura-2), and secretion of immunoreactive CGRP and CT have been investigated in rat and human MTC cell lines. Rat MTC 6-23 cells responded to a rise in [Ca2+](e) from 0.5 to 3.0 mM with a transient increase of [Ca2+](i), and the secretion of CGRP and CT was raised from 19 ± 2 (mean ± SE) to 122 ± 28 pg rat CGRP/mg protein·min and from 33 ± 8 to 155 ± 42 pg rat CT/Mg protein·min (P < 0.01). In the human MTC (TT) cell line, a rise of [Ca2+](e) from 0.5 to 3.0 mM did not affect [Ca2+](i), and the secretion of CGRP and CT remained unchanged at 7.0 ± 1.1 ng CGRP/mg protein·min and 1.0 ± 0.1 ng CT/mg protein·min. However, when the plasma membrane was bypassed by electropermeabilization, the release of CGRP and CT was stimulated by calcium with an ED50 of 0.5 μM and 0.3 μM, respectively. With ionomycin, the secretion of CGRP and CT was also stimulated up to 17-fold in [Ca2+](i)-dependent manner. The results indicate a role of [Ca2+](i) in the secretion of CGRP and CT and provide evidence for a defect in Ca2+ signal transduction in the human MTC cell line.
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