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Human angiotensin II type 1 receptor isoforms encoded by messenger RNA splice variants are functionally distinct
M M Martin1, B M Willardson, G F Burton
1Department of Chemistry and Biochemistry, Brigham Young University, P.O. Box 25700, Provo, Utah 84602, USA.
Molecular Endocrinology (Baltimore, Md.)
|February 7, 2001
Summary
Researchers discovered a new long human angiotensin II type 1 receptor (hAT(1)R) isoform. This long hAT(1)R variant has lower affinity for angiotensin II, impacting cellular responses and fine-tuning tissue sensitivity.
Area of Science:
- Molecular Biology
- Biochemistry
- Pharmacology
Background:
- Human tissues express four distinct alternatively spliced human angiotensin II type 1 receptor (hAT(1)R) mRNA transcripts.
- The varying abundance of these transcripts across tissues suggests functional differences between splice variants.
Purpose of the Study:
- To identify and characterize novel hAT(1)R splice variants.
- To investigate the functional differences between short and long hAT(1)R isoforms.
Main Methods:
- Analysis of hAT(1)R mRNA splice variants in human tissues.
- In vivo characterization of hAT(1)R isoform function.
- Assessment of Ang II binding affinity and downstream signaling (inositol trisphosphate production, Ca(2+) mobilization).
Main Results:
- The hAT(1)R-B mRNA splice variant encodes a novel long hAT(1)R isoform.
- This long hAT(1)R isoform exhibits significantly diminished affinity for Ang II (>3-fold reduction) compared to the short hAT(1)R isoform (encoded by hAT(1)R-A).
- The long hAT(1)R isoform shows a rightward shift in dose-response curves for Ang II-induced inositol trisphosphate production and Ca(2+) mobilization.
Conclusions:
- A novel long hAT(1)R isoform with reduced Ang II affinity exists in vivo.
- Functional differences between short and long hAT(1)R isoforms enable fine-tuning of Ang II responsiveness.
- Regulation of hAT(1)R isoform abundance provides a mechanism for tissue-specific control of Ang II signaling.