The Signal Transduction Pathways Of Imidazoline-1 Receptor Candidate Protein

Imidazoline-1 receptor (I1R) is a kind of novel receptor which participates in many physiological functions. In 2000, cDNA encoding imidazoline-1 receptor (I1R) candidate protein, named imidazoline receptor antisera-selected protein (IRAS), was cloned from human hippocampus. IRAS provides the basis for further studying the function and cell signal transduction pathway of I1R.In the present study, the signal transduction pathway of I1R was studied in CHO cells stably transfected with IRAS (CHO-IRAS). I1R agonists rilmenidine, moxonidine and agmatine, an endogenous I1R ligand, failed to stimulate [35S]-GTPγS binding in CHO-IRAS cells. Therefore, IRAS may not be a G protein coupled receptor (GPCR). Rilmenidine, moxonidine and agmatine increased the activation of phosphatidylcholine selective phospholipase C (PC-PLC) in concentration and time-dependent model in CHO-IRAS cells, which was followed by diacylglyceride (DAG) accumulation. I1R selective antagonist efaroxan and the PC-PLC inhibitor D609, reversed the increase in the activity of PC-PLC stimulated by rilmenidine, moxonidine and agmatine. Rilmenidine and moxonidine stimulated the phosphorylation of extracellular signal-regulated kinase (ERK) in CHO-IRAS cells by concentration-dependence. However, agmatine had dual effect on ERK phosphorylation. Agmatine increased ERK phosphorylation at high concentration (10 μM -100 μM), and decreased ERK phosphorylation at low concentration (1 nM -10 nM). Efaroxan and D609 blocked the effect of rilmenidine, moxonidine and agmatine on ERK phosphorylation.In conclusion, IRAS may not be a GPCR. The signal transduction pathway of IRAS can be summarized as follows: binding of I1R agonists such as rilmenidine, could stimulate PC-PLC activity, PC-PLC in turn, using PC as substrate, could increase the accumulation of DAG, and further activated MAPK cascades.