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

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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.