Human angiotensin II type 1 receptor isoforms encoded by messenger RNA splice variants are functionally distinct

Human tissues that express the angiotensin II (Ang II) type 1 receptor(hAT( 1)R) can synthesize four distinct alternatively spliced hAT(1)R mRNA transc ripts. In this study, we show that the relative abundance of these mRNA tra nscripts varies widely in human tissues, suggesting that each splice varian t is functionally distinct. Here we demonstrate, for the first time, that t he hAT(1)R-B mRNA splice variant encodes a novel long hAT(1)R isoform in vi vo that has significantly diminished affinity for Ang II (i.e. >3-fold) whe n compared with the short hAT(1)R isoform (encoded by hAT(1)R-A mRNA splice variant). This reduced agonist affinity caused a significant shift to the right in the dose-response curve for Ang II-induced inositol trisphosphate production and Ca2+ mobilization of the long hAT(1)R when compared with tha t of the short hAT(1)R. The functional differences between these isoforms a llows Ang II responsiveness to be fine-tuned by regulating the relative abu ndance of the long and short hAT(1)R isoform expressed in a given human tis sue.