Endocrine Signaling Group, Comparative Biomedical Sciences, Royal Veterinary College, University of London, Royal College Street, London, NW1 0TU, UK.
Cell Tissue Res. 2014 Feb;355(2):425-36. doi: 10.1007/s00441-013-1763-y. Epub 2013 Dec 20.
The guanylyl cyclases, GC-A and GC-B, are selective receptors for atrial and C-type natriuretic peptides (ANP and CNP, respectively). In the anterior pituitary, CNP and GC-B are major regulators of cGMP production in gonadotropes and yet mouse models of disrupted CNP and GC-B indicate a potential role in growth hormone secretion. In the current study, we investigate the molecular and pharmacological properties of the CNP/GC-B system in somatotrope lineage cells. Primary rat pituitary and GH3 somatolactotropes expressed functional GC-A and GC-B receptors that had similar EC50 properties in terms of cGMP production. Interestingly, GC-B signaling underwent rapid homologous desensitization in a protein phosphatase 2A (PP2A)-dependent manner. Chronic exposure to either CNP or ANP caused a significant down-regulation of both GC-A- and GC-B-dependent cGMP accumulation in a ligand-specific manner. However, this down-regulation was not accompanied by alterations in the sub-cellular localization of these receptors. Heterologous desensitization of GC-B signaling occurred in GH3 cells following exposure to either sphingosine-1-phosphate or thyrotrophin-releasing hormone (TRH). This heterologous desensitization was protein kinase C (PKC)-dependent, as pre-treatment with GF109203X prevented the effect of TRH on CNP/GC-B signaling. Collectively, these data indicate common and distinct properties of particulate guanylyl cyclase receptors in somatotropes and reveal that independent mechanisms of homologous and heterologous desensitization occur involving either PP2A or PKC. Guanylyl cyclase receptors thus represent potential novel therapeutic targets for treating growth-hormone-associated disorders.
鸟苷酸环化酶，GC-A 和 GC-B，是心房和 C 型利钠肽（ANP 和 CNP，分别）的选择性受体。在前垂体中，CNP 和 GC-B 是促性腺激素中 cGMP 产生的主要调节剂，但 CNP 和 GC-B 破坏的小鼠模型表明它们在生长激素分泌中可能具有作用。在本研究中，我们研究了 CNP/GC-B 系统在生长激素细胞中的分子和药理学特性。原代大鼠垂体和 GH3 生长激素细胞表达功能性 GC-A 和 GC-B 受体，它们在 cGMP 产生方面具有相似的 EC50 特性。有趣的是，GC-B 信号以蛋白磷酸酶 2A（PP2A）依赖性方式快速发生同源脱敏。慢性暴露于 CNP 或 ANP 以配体特异性方式导致 GC-A 和 GC-B 依赖性 cGMP 积累的显著下调。然而，这种下调并不伴随着这些受体亚细胞定位的改变。GH3 细胞中 GC-B 信号的异源脱敏在暴露于 1-磷酸鞘氨醇或促甲状腺素释放激素（TRH）后发生。这种异源脱敏是蛋白激酶 C（PKC）依赖性的，因为 GF109203X 的预处理可防止 TRH 对 CNP/GC-B 信号的影响。总的来说，这些数据表明生长激素细胞中颗粒鸟苷酸环化酶受体具有共同和独特的特性，并表明同源和异源脱敏的独立机制涉及 PP2A 或 PKC。鸟苷酸环化酶受体因此代表了治疗生长激素相关疾病的潜在新的治疗靶点。
