Heterodimers – a new dimension in disease

Abstract

The pharmacology of G-protein-coupled receptor heterodimers is a relatively new area of scientific investigation. Several examples of functional heterodimers with distinct pharmacological properties have been identified, and it is probably only a matter of time before many more follow in their wake. However, the prospect of investigating all the potential interactions is a daunting one, with the number of possible combinations clearly enormous. Although the potential ramifications of GPCR heterodimerization have been previously recognized, a recent study has provided the first evidence that altered function, as a consequence of receptor heterodimerization, is a significant contributor to the pathophysiology of a serious clinical condition.AbdAlla et al.1xIncreased AT1 receptor heterodimers in preeclampsia mediate enhanced angiotensin II responsiveness. AbdAlla, S. et al. Nat. Med. 2001; 7: 1003–1009Crossref | PubMed | Scopus (303)See all References1 have characterized the heterodimers formed between the AT1 receptor for angiotensin II and the B2 receptor for bradykinin in the platelets and omental vessels of normotensive and preeclamptic pregnant women. The investigation starts with the observation that preeclamptic women are hypersensitive to the pressor effects of angiotensin II, even though they show no increase in levels of either AT1 receptor or circulating angiotensin II itself. However, they have shown that in preeclamptic women there is a fivefold rise in the levels of the B2 receptor, and while levels of the AT1 receptor remain the same, there is a similar increase in levels of AT1–B2 heterodimers. Furthermore, this increase is associated with enhanced angiotensin II-induced Ca2+ mobilization in platelets from affected women and an increase in G-protein activation.A further feature of both normal and preeclamptic pregnancy is a rise in levels of oxidative stress. AbdAlla et al. investigated the effect of H2O2 on the function of normal and heterodimerized receptors. They showed that H2O2 was able to induce homodimerization of AT1 receptors and that this was associated with a blunting of the responsiveness of the receptor to activation by angiotensin II. However, levels of preformed AT1–B2 heterodimers were unaffected by H2O2 and the enhanced responsiveness to angiotensin remained the same. It is possible, therefore, that the increase in heterodimerization that results as a consequence of the upregulation of the B2 receptors, could reduce the effectiveness of the oxidative mechanisms that control blood pressure in pregnancy, leading to the hypertension characteristic of preeclampsia.In this postgenomic era it is becoming increasingly clear that biological function, even in isolated cells, let alone entire organisms, cannot simply be predicted by reference to gene expression and a knowledge of the function of individual proteins. Interactions between proteins occur at every level of biological organization, and a full understanding of cellular function will require an appreciation of the role played by these interactions. Distinct, isolated receptors and clearly defined signaling pathways no longer provide an adequate paradigm, and the era of complex networks of interactions is very much here, opening up a whole new dimension for investigation with endless possibilities for our understanding of physiology and ultimately our ability to intervene and treat disease. Preeclampsia is one of the most serious complications of pregnancy in the developed world and claims the lives of mothers and unborn children every year. It can only be hoped that this step forward in our understanding will ultimately result in the saving of some of those precious lives.