Key result
Treatment with AT1 receptor antagonists increased the binding ability of the C18S mutant to AngII and reduced enhanced basal IP3 levels, suggesting constitutive internalization.
Disruption of the Cys18-Cys274 bond in the AT1 receptor leads to an active-like conformation that favors constitutive internalization in the absence of agonist.
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No clinical implications for AT1 antagonist use; leaves open mechanistic roles of AT1 receptor conformation in human disease.
Previous research showed that disruption of the Cys(18)-Cys(274) bond in the angiotensin II (AngII) AT₁ receptor mutant (C18S), expressed in CHO cells, causes an increase in the basal activity and attenuation of the maximum response to AngII. In addition, this mutant was mostly intracellularly distributed. Our aim was to investigate whether the intracellular presence of the mutant was due to a constitutive internalization or to a defective maturation of the receptor. The first hypothesis was assessed by pretreating the cells with losartan or [Sar¹Leu⁸]-AngII, specific AT₁ receptor antagonists, a maneuver to revert the receptor internalization. The second hypothesis was tested using calnexin, an endoplasmic reticulum marker. We found that treatment with AT₁ receptor antagonists causes an increase in the binding ability of the mutant to AngII. Furthermore, whereas the maximum effect is increased, it reduces the enhanced basal levels of IP₃. The hypothesis for a lack of maturation of the mutant receptor was ruled out because calnexin was poorly colocalized with the intracellular C18S receptor. Our results suggest that the mutation of the AT₁ receptor leads to a conformational structure similar to that of the active mode of the AT₁ receptor, favoring its internalization in the absence of the agonist.
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Martin et al. (2010) studied this question. AT1 receptor antagonists (losartan or [Sar¹Leu⁸]-AngII) was evaluated on Binding ability of the mutant to AngII and basal levels of IP3. Treatment with AT1 receptor antagonists increased the binding ability of the C18S mutant to AngII and reduced enhanced basal IP3 levels, suggesting constitutive internalization.
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