Unexpected Observations on the Receptors for Angiotensin Ⅱ

다국어 초록 (Multilingual Abstract)

The renin-angiotensin system(RAS) is a master control switch in the regulation of blood pressure. Transgenic and gene knockout mouse model studies as well as the effectiveness of RAS inhibitors in controlling essential hypertension and heart failure establish the importance RAS in the pathogenesis of cardiovascular disease. The octapeptide hormone angiotensin Ⅱ(Ang Ⅱ) is the mediator of RAS functions. The cell surface receptors for Ang Ⅱ belong to seven transmembrane(7TM) helical receptor superfamily. 7TM receptors are conformational switches that couple a wide variety of external stimuli to intracellular signal transduction pathways via heterotrimeric G-proteins to modulate cellular functions. To understand the mechanism of activation of function in the Ang Ⅱ type-1(AT1) and type-2 receptors, we have systematically studied structural analogs of Ang Ⅱ in combination with site-directed mutants of the receptors. Our studies suggest that conformation of the unliganded Ang Ⅱ type 1(AT1) and type 2(AT2) receptors are distinctly different. The AT1 receptor is prototypical: in that the unliganded receptor is in an inactive state(R), and the transition to a functionally active state(R*) requires the binding of the hormone to the transmembrane domain of the receptor. The bound hormone, generates an unconstrained intermediate state(R') which partially conforms to the R* state. In contrast, the unliganded AT2 receptors are in the R' state.
Despite the importance of Ang Ⅱ receptors in human disease process, familial mutations of RAS have not been found implying that either such mutations are embryonic lethal or unknown mechanisms may exist in vivo for masking defective RAS phenotypes. In some studies, molecular variants of RAS have been implicated in the inherited predisposition towards cardiovascular disease. Our objectives are to study the association of genetic variability of Ang Ⅱ receptors with cardiovascular disease. We will discuss the results obtained from these two projects.
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This work was supported by grants HL57470 from the NIH and an Established Investigator A ward from the American Heart Association.