Expression of thyrotropin-releasing hormone receptor in immortalized beta-cell lines and rat pancreas

Abstract

Thyrotropin-releasing hormone (TRH), a hypothalamic tripeptide, is expressed in pancreatic islets at peak levels during the late gestation and early neonate period. TRH increases insulin production in cultured -cells, suggesting that it might play a role in regulating pancreatic -cell function. However, there is limited information on TRH receptor expression in the pancreas. The aim of the present study was to explore the distribution of the TRH receptor in the pancreas and its function in pancreatic -cells. TRH receptor type 1 (TRHR1) gene expression was detected by RT-PCR and verified by Northern blotting and immunoblotting in the -cell lines, INS-1 and TC-6, and the rat pancreatic organ. The absence of TRH receptor type 2 expression in the tissue and cells indicated the tissue specificity of TRH receptor expression in the pancreas. The TRHR1 signals (detected by in situ hybridization) were distributed not only in islets but also in the surrounding areas of the pancreatic ductal and vasal epithelia. The apparent dissociation constant value for the affinity of [ 3 H]3-methyl-histidine TRH (MeTRH) is 4·19 in INS-1 and 3·09 nM in TC-6. In addition, TRH induced epidermal growth factor (EGF) receptor phosphorylation with a half-maximum concentration of approximately 50 nM, whereas the high affinity analogue of TRH, MeTRH, was 1 nM. This suggested that the affinity of TRH ligands for the TRH receptor influences the activation of EGF receptor phosphorylation in TC-6 cells. Our observations suggested that the biological role of TRH in pancreatic -cells is via the activation of TRHR1. Further research is required to identify the role of TRHR1 in the pancreas aside from the islets.

The molecular mechanism of EGF receptor activation in pancreatic β-cells by thyrotropin-releasing hormone

“…TRH initiated EGF receptor phosphorylation, which may be through the TRHR1 receptor paracrine effect in ␤-cells. A higher-affinity MT-TRH (TRH analog) induced stronger EGF receptor phosphorylation than native TRH (21), which fits the notion that the TRH stimulation of EGF phosphorylation depends on TRH receptor-activation. TRH binds to its receptor, causing dissociation of the ␣-and ␤␥-G protein subunit and thus triggering signal cascades after GPCR activation (Fig.…”

“…The delay in the EGF receptor phosphorylation response to TRH compared with EGF indicates that there are several different mechanisms between TRH and EGF for EGF receptor activation. It is unclear whether TRH phosphorylates the EGF receptor through TRHR1 (21) or -R2 (37). TRHR1 has been found in the mouse pancreas, but no references were reported as to but had no effect on Tyr 1068 phosphorylation (middle).…”

TRH-Receptor-Type-2-Deficient Mice are Euthyroid and Exhibit Increased Depression and Reduced Anxiety Phenotypes

“…In contrast, TRH-R2-knockout mice exhibit normal glucose homeostasis even when given a high fat diet. Therefore, TRH regulation of glucose metabolism in rodents (Kulkarni et al , 1995; Yamada et al , 2000; Luo and Yano, 2004) is mediated by TRH-R1. Furthermore, it was suggested that the effect of TRH on glucose homeostasis is mediated, at least in part, by TRH-R1 expressed on insulin-secreting cells.…”

High Levels of Thyrotropin-Releasing Hormone Receptors Activate Programmed Cell Death in Human Pancreatic Precursors

“…Indeed, electron microscopy has revealed that TRH is co-localized with insulin in secretory granules in β cells in fetal rat islets (17,18). In contrast, it is controversial whether TRHRs are expressed in the normal pancreas (12,13) even though several lines of evidence suggest a possible pancreatic role for TRHR signaling (19). Perhaps the most compelling data in this regard are the alterations in glucose homeostasis that were observed in TRH-knockout mice (20) that are consistent with the idea that the TRH/TRHR system plays a role in embryonic development or adult function of β cells, or both.…”