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

Abstract

Objectives Thyrotropin-releasing hormone (TRH) is expressed in rodent and human adult pancreas, and in mouse pancreas during embryonic development. However, expression of TRH receptors (TRHRs) in the pancreas is controversial. We sought to provide evidence that the TRH/TRHR system might play a role in fetal development. Methods We used quantitative RT-PCR to measure TRH and TRHR mRNA. To study the effects of TRHR expression in a pancreatic progenitor population, we expressed TRHRs in human islet-derived precursor cells (hIPCs) by infection with adenoviral vector AdCMVmTRHR. TRHR signaling was measured as inositol phosphate production and intracellular calcium transients. TRHR expression was measured by [3H]methyl-TRH binding. Apoptosis was monitored by release of cytochrome C from mitochondria. Results We show that TRH mRNA is expressed in human fetal and adult pancreas, and that TRHR mRNA is expressed in fetal human pancreas but not in adult human pancreas. TRHRs expressed in hIPCs were shown to signal normally. Most importantly, TRH treatment for several days stimulated apoptosis in hIPCs expressing approximately 400,000 TRHRs per cell. Conclusions These findings suggest a possible role for TRH/TRHR signaling in pancreatic precursors to promote programmed cell death, a normal constituent of morphogenesis during embryonic development in humans.

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

“…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. It is noteworthy, therefore, that although TRH-R1 has been reported to be expressed in adult rodent islets at the mRNA and protein levels ( Kulkarni et al , 1995 ; Luo and Yano, 2004 ), we have found no TRH-R mRNA in islets of Langerhans from adult humans ( Mulla et al , 2008 ).…”

The syndrome of central hypothyroidism and macroorchidism: IGSF1 controls TRHR and FSHB expression by differential modulation of pituitary TGFβ and Activin pathways

“…On the other hand, TRHR is expressed not only in the pituitary but also in other tissues, including the testis 62 63 . Therefore, a possible contribution of altered paracrine action of TRH on testicular TRHR in the absence of IGSF1 may deserve consideration.…”

Identification and subcellular localization of molecular complexes of G<sub>q/11</sub>α protein in HEK293 cells

“…A relatively high (10 mM) TRH concentration mostly used in the present work is not physiological and it may potentially cause cell damage or death [37]. However, we have previously found that the addition of 10 mM TRH to the HEK293 cell line stably expressing TRH-R1 and G 11 m protein does not lead to apoptosis, although the cells stop growing [38].…”