Molecular cloning and pharmacological characterization of an atypical gerbil angiotensin II type-1 receptor and its mRNA expression in brain and peripheral tissues

In the gerbil brain, most of the [I-125]Sarcosine(1)-Angiotensin II binding sites are atypical, not sensitive to displacement with selective Angiotensin II AT(1) and AT(2) receptor ligands. A similar atypical binding profile exists in the gerbil kidney, where binding is highly expressed. We isolated a 2197 base pair clone from a gerbil kidney cDNA library which encodes a 359 amino acid protein with higher than 90% homology to other mammalian angiotensin II AT(1) receptors. When expressed in COS-7 cells, stimulation by Angiotensin Il of both the cloned gerbil receptor or the human AT(1) receptor enhanced TP, production to a similar degree. In COS-7 cells, the gerbil receptor also had a ligand affinity profile similar to that of the human AT(1) receptor, but showed greatly reduced affinity for losartan (IC50 = 3480 +/- 174 nM). In the gerbil brain, in situ hybridization revealed receptor mRNA in circumventricular organs, selective hypothalamic, midbrain and brain stem areas, and in the hippocampus, where high mRNA expression was detected in the stratum pyramidale of the CA1 and CA2 subfields, and in the stratum granulosum of the dentate gyrus. The expression pattern of receptor mRNA corresponded well with that of atypical [I-125]Sar(1)-Ang II binding. In situ hybridization and Southern blot experiments using riboprobes against the open reading frame and the 3'-untranslated region of the cloned gerbil Ang II receptor cDNA suggest that gerbils have, like other rodents, two AT(1) receptor subtypes. The receptor mRNA distribution of the cloned gerbil Ang II receptor corresponds to the distribution of AT(1A) receptors described in other rodent species. (C) 1998 Elsevier Science B.V. All rights reserved.