Regulatory mechanisms of signaling pathways through GnRH receptor heterodimerization with a species-specific orphan receptor subtype

四种GnRH受体（Ci-GnRHR1-4）在原棘猴（Ciona nestiinalis）中被鉴定出来。ciona特异性GnRHR类似物Ci-GnRHR4 （R4）一直被认为是孤儿或无功能受体。在卵巢和转染的HEK293MSR细胞中检测到R1和R4之间的二聚体。R1与R4的异二聚化导致tGnRH-6对Ca <2+>依赖性的PKC<的激活增强，tGnRH-5和6对Ca <2+>依赖性的PKC的激活增强，最终导致MAPK级联中ERK磷酸化上调。这些结果证明，R4作为内源性调节因子通过与R1异源二聚化对信号转导进行微调，并且GPCR与孤儿受体异源二聚化参与了一种在生物体中广泛保守的独特信号级联调节模式的进化。

Four GnRH receptors (Ci-GnRHR1-4) were identified in the protochordate, Ciona intestinalis. A Ciona-specific GnRHR paralog, Ci-GnRHR4 (R4) has been regarded as an orphan or non-functional receptor. The dimerization between R1 and R4 in the ovary and in the transfected HEK293MSR cells was detected. The heterodimerization of R1 with R4 led to potentiation of Ca^<2+>-dependent activation of PKC< by tGnRH-6 and Ca^<2+>-independent activation of PKC by tGnRH-5 and 6, eventually leading to up-regulation of ERK phosphorylation in the MAPK cascade. These results provide evidence that R4 serves as an endogenous modulatory factor for the fine-tuning of signal transduction via heterodimerization with R1, and that GPCR heterodimerization with an orphan receptor is involved in the evolution of a unique pattern of signaling cascade regulation widely conserved in organisms.