GPCR-aggregation

More than a decade ago, we initiated a paradigm shift in GPCR pharmacology, by the identification of a protein complex formed between the receptor for the vasopressor angiotensin II AT1 receptor with the vasodepressor bradykinin B2 receptor external page(Nature 2000, 407, 94-98). The AT1R-B2R aggregate is the first example of pathophysiological GPCR dimerization external page(Nature Medicine 2001, 7, 1003-1009) and contributes to the symptoms of hypertensive disorders, e.g. preeclampsia hypertension of patients and experimental hypertension.

Our initial findings were confirmed in 2013 by an independent research team at the University of South Carolina, USA external page(J. Biol. Chem. 2013, 288, 18872-18884). Moreover, the US research team found that a new class of biased agonists can target the AT1R-B2R heteromer pharmacologically.

Enlarged view: GPCR-aggregation
The mechanism of action of a biased agonist targeting the AT1R-B2R heterodimer

More information on AT1R-B2R heterodimerization external pagecan be found here.

To further analyse the in vivo function of the AT1R-B2R complex, we generated transgenic models with and without AT1R-B2R heteromerization. The models revealed the physiological function of AT1R-B2R heterodimerization in angiotensin II-stimulated blood pressure control.

 

 

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