Effects of glucagon and glucagon-like peptide-1-(7-36) amide on C cells from rat thyroid and medullary thyroid carcinoma CA-77 cell line

Glucagon is known to stimulate calcitonin secretion by thyroid C cells over a nide range of concentrations, raising the possibility of its interaction with several types of receptors. This study was designed to characterize receptors that mediate the effect of glucagon on a rat C cell line (CA-77). Binding studies, using radiolabeled [I-125]glucagon and [I-125]glucagon-like peptide-1-(7-36) amide ([I-125]tGLP-1), to CA-77 plasma membranes demonstrated the presence of 1) a glucagon receptor with a dissociation constant (K-d) of 2.3 nM and relative potencies for structurally related peptides as follows: glucagon > oxyntomodulin >> tGLP-1; and 2) a tGLP-1 receptor with a K-d of 0.33 nM and relative potencies as follows: tGLP-1 > oxyntomodulin > glucagon. Glucagon stimulated calcitonin secretion from CA-77 cells in a dose-dependent manner over 4 orders of magnitude, with a maximal response of 312% over the basal value and an ED(50) dose to 50 nM. tGLP-1 induced a calcitonin release over 2 orders of magnitude, with a maximal response of 170% over the basal value and an ED(50) close to 0.2 nM. Glucagon and tGLP-1 stimulated cAMP production in CA-77 cells to similar maximal levels over 4 and 2 orders of magnitude, respectively. The stimulation of cAMP production by glucagon at concentrations over 10 nM was suppressed by the tGLP-1 antagonist exendin-(9-39) amide, whereas the stimulation of calcitonin secretion was only partly abolished. Using a perifusion system of rat thyroid, glucagon and tGLP-1 stimulated calcitonin secretion in a calcium-dependent manner. It is concluded that glucagon and tGLP-1 receptors are expressed in the rat C cell line (CA-77) and in the normal rat thyroid. The effects of glucagon on calcitonin secretion observed at high concentrations are mediated in part through interaction with tGLP-1 receptors and via an additional non-cAMP-mediated mechanism.