Neuregulin 1 mitigated prolactin deficiency through enhancing TRPM8 signaling under the influence of melatonin in senescent pituitary lactotrophs

• Published in: International journal of biological macromolecules 2024-08, Vol.275 (Pt 1), p.133659, Article 133659
• Main Authors: Zhang, Wei, Dao, Ji-ji, Li, Qian, Liu, Chong, Qiao, Chen-meng, Cui, Chun, Shen, Yan-qin, Zhao, Wei-jiang
• Format: Article
• Language: English
• Subjects: Aging - metabolism; Animals; Cell Line; cell lines; Cell senescence; Cellular Senescence - drug effects; Female; fluorescent antibody technique; galactose; Humans; ion channels; Lactotrophs - drug effects; Lactotrophs - metabolism; Male; Melatonin; Melatonin - pharmacology; microarray technology; Neuregulin-1 - genetics; Neuregulin-1 - metabolism; neurotrophins; Nrg1; Pituitary Gland - drug effects; Pituitary Gland - metabolism; Pituitary lactotroph cells; PRL; prolactin; Prolactin - metabolism; Rats; Receptor, ErbB-4 - genetics; Receptor, ErbB-4 - metabolism; secretion; Signal Transduction - drug effects; subfamily; TRPM Cation Channels - genetics; TRPM Cation Channels - metabolism; TRPM8
• ISSN: 0141-8130; 1879-0003; 1879-0003
• DOI: 10.1016/j.ijbiomac.2024.133659

The age-related alterations in pituitary function, including changes in prolactin (PRL) production contributes to the systemic susceptibility to age-related diseases. Our previous research has shown the involvement of Nrg1 in regulating the expression and secretion of PRL. However, the precise role of Nrg1 in mitigating the senescence of pituitary lactotrophs and the underlying mechanisms are yet to be comprehended. Here, data from the GEPIA database was used to evaluate the association between transient receptor potential cation channel subfamily M member 8 (TRPM8) and PRL in normal human pituitary tissues, followed by immunofluorescence verification using a human pituitary tissue microarray. TRPM8 levels showed a significant positive association with PRL expression in normal human pituitary tissues, and both TRPM8 and PRL levels declined during aging, suggesting that TRPM8 may regulate pituitary aging by affecting PRL production. It was also found that treatment with exogenous neuregulin 1 (Nrg1) markedly delayed the senescence of GH3 cells (rat lactotroph cell line) generated by D-galactose (D-gal). In addition, melatonin reduced the levels of senescence-related markers in senescent pituitary cells by promoting Nrg1 / ErbB4 signaling, stimulating PRL expression and secretion. Further investigation showed that Nrg1 attenuated senescence in pituitary cells by increasing TRPM8 expression. Downregulation of TRPM8 activation eliminated Nrg1-mediated amelioration of pituitary cell senescence. These findings demonstrate the critical function of Nrg1 / ErbB signaling in delaying pituitary lactotroph cell senescence and enhancing PRL production via promoting TRPM8 expression under the modulation of melatonin.