Neuroendocrine regulation and transduction mechanisms in pituitary hormone release in fish

鱼类垂体激素释放的神经内分泌调节和转导机制

• 批准号: RGPIN-2015-05636
• 负责人: Chang, John
• 金额: $ 3.57万
• 依托单位: University of Alberta
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2020
• 资助国家: 加拿大
• 起止时间: 2020-01-01 至 2021-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=708662
• 关键词: Neuroendocrine; regulation; transduction; mechanisms; pituitary

Pituitary luteinizing hormone (LH) and growth hormone (GH) are important regulators of reproduction and growth in vertebrates. Multiple stimulatory and inhibitory brain hypothalamic neurohormones in turn control LH and GH secretion and production. Thus, studying the mechanisms by which the effects of these neurohormones are manifested at the level of the pituitary cells is important for understanding the physiological control of growth and reproduction. In goldfish, LH- and GH-cells share common, as well as distinct, regulators. For example, two gonadotropin-releasing hormones (GnRH2 and GnRH3), pituitary adenylate cyclase-activating polypeptide (PACAP) and ghrelin (gGRLN) stimulate both LH and GH secretion while dopamine (DA) inhibits LH, but stimulates GH, release. In contrast, GH-releasing hormone (gGHRH) stimulates GH, but attenuates LH, secretion. Understanding how the intracellular cellular changes (signal tranduction events) effected by these neurohormones interact to mediate their influences on LH and GH release and synthesis is integral to studying the physiological control of reproduction and growth. We have previously focused on how extracellular and intracellular Ca2+, protein kinase A (PKA), PKC, nitric oxide, extracellular-regulated kinase (ERK), phosphoinositide 3-kinase (PI3K) mediate the neuroendocrine control of LH and GH secretion and synthesis in goldfish pituitary cells. Using dispersed goldfish pituitary cells in primary culture, this grant proposal focuses on: 1) whether intracellular Ca2+ stores, PI3K and ERK mediate gGRLN actions on LH- and GH-cells, and how gGRLN receptor expression is affected by GnRH, DA, PACAP and gGHRH treatments; 2) the mechanisms mediating gGHRH stimulation of GH secretion and its novel inhibitory influence on LH release; 3) the transduction pathways mediating the LH and GH release responses to two goldfish kisspeptins, peptides that are thought to be involved in the regulation of puberty in vertebrates; 4) the mechanisms by which goldfish gonadotropin-inhibitory hormone exerts its seasonal-dependent inhibitory and stimulatory effects on hormone release and synthesis in LH- and GH-cells; 5) how PI3K interacts with other signal transduction components in mediating LH and GH release and synthesis, and in particular the differential actions of GnRH2 and GnRH3 on these processes; and 6) the differential expression and role of two known goldfish GnRH receptor isoforms on LH- and GH-cells. Results will contribute to our understanding of how neuroendocrine control of goldfish LH- and GH-cell functions are mediated and integrated, as well as the regulation control of growth and reproduction in goldfish and other teleosts, including important aquaculture species (such as cyprinids). Results will also be important for the basic understanding of ligand- and function-specific intracellular signaling in general.

脑垂体促黄体生成素(LH)和生长激素(GH)是脊椎动物生殖和生长的重要调节因子。大脑下丘脑的多种刺激和抑制神经激素依次控制黄体生成素和生长激素的分泌和产生。因此，研究这些神经激素在脑垂体细胞水平上的作用机制，对于理解生长和生殖的生理控制是很重要的。在金鱼中，黄体生成素和生长激素细胞既有共同的，也有不同的调节因子。例如，两种促性腺激素释放激素(GnRH2和GnRH3)，垂体腺苷酸环化酶激活多肽(PACAP)和Ghrelin(GGRLN)刺激黄体生成素和生长激素的分泌，而多巴胺(DA)抑制黄体生成素，但刺激生长激素的释放。相反，生长激素释放激素(GGHRH)刺激生长激素，但抑制促黄体生成素的分泌。了解这些神经激素如何影响细胞内的变化(信号转导事件)，从而调节它们对黄体生成素和生长激素的释放和合成的影响，对于研究生殖和生长的生理控制是不可或缺的。我们以前的研究主要集中在细胞外和细胞内的钙离子、蛋白激酶A(PKA)、蛋白激酶C(PKC)、一氧化氮(NO)、细胞外调节的激酶(ERK)、磷脂酰肌醇3-激酶(PI3K)如何介导神经内分泌对金鱼脑垂体细胞分泌和合成黄体生成素和生长激素的调控。 利用分散的金鱼脑垂体细胞进行原代培养，这项资助建议集中在：1)细胞内钙库、PI3K和ERK是否介导了gGRLN对黄体生成素和生长激素细胞的作用，以及GnRH、DA、PACAP和gGHRH处理对gGRLN受体表达的影响；2)gGHRH刺激生长激素分泌的机制及其对黄体生成素释放的新的抑制作用；3)两种被认为参与脊椎动物青春期调节的多肽对黄体生成素和生长激素释放反应的信号转导途径；4)金鱼促性腺激素抑制激素对黄体生成素和生长激素释放和合成的季节性抑制和刺激作用的机制；5)PI3K如何与其他信号转导成分相互作用调节黄体生成素和生长激素的释放和合成，特别是GnRH2和GnRH3在这些过程中的不同作用；以及6)已知的两种金鱼促性腺激素受体亚型在黄体生成素和生长激素细胞上的差异表达和作用。这些结果将有助于我们理解神经内分泌控制金鱼的黄体生成素和生长激素细胞功能是如何调节和整合的，以及金鱼和其他硬骨鱼，包括重要的水产养殖物种(如鲤鱼)生长和繁殖的调控。结果也将是重要的基本理解的配基和功能的细胞内信号一般。