The
Dupré laboratory
Research Interests
The overall objectives of the research of my laboratory are to:a) characterize the events leading to the assembly of the various homo- and heterodimeric receptors and their specific targetting to plasma membrane,
b) identify the molecular chaperones involved in the assembly and selection of the partners of the specific signalling complexes, and
c) identify, among different subpopulations of receptor-based signalling complexes existing simultaneously (homo- versus heterodimeric receptor complexes), unique interactors of interest as therapeutic targets.
All these objectives have one common goal: to identify the mechanisms leading to 7TM-R specificity of signalling.
Seven transmembrane receptors (7TM-Rs) are the largest family of plasma membrane receptors and couple to G proteins to activate downstream signalling pathways that give rise to alterations in cell function and gene expression. More than 30% of currently marketed prescription drugs directly or indirectly target these systems and, account for more than $20 billion of annual sales worldwide. Furthermore, the potential for additional therapeutic strategies that target these systems is considerable; currently available drugs target pathways that are controlled by only 10% of human 7TM-Rs (of approximately 800 in total) that have been identified thus far.
Diversity in signalling arises, in part, via the coupling of 7TM-Rs to different G proteins; for example, beta-adrenergic and angiotensin type II AT1 receptors are both 7TM-Rs but are not coupled to the same G protein (Gs/i for beta2AR and Gq/i for AT1R) giving rise to distinct pharmacology. Although receptors of this family were initially thought to function as monomeric entities, it is now generally accepted that they exist as homo- and heterodimers, the existence of which may give rise to novel pharmacology. In support of this, AT1R was shown to undergo homo- and heterodimerization with many other receptors, including bradykinin B2, beta2-adrenergic and dopamine D2 receptors. The fact that beta2AR and AT1R can interact directly may have profound consequences on the overall response to drugs that target these receptors. Recent work has shown that treatment of mice with valsartan, an AT1R blocker, resulted in a significant reduction in the maximal response to catecholamine-induced elevation of the heart rate. Also, adverse effects were observed in clinical trials with a combination of valsartan, beta-blockers and ACE inhibitors. A treatment with valsartan and a beta-blocker would have a near complete inhibition of signalling pathways of both receptors of an AT1R/beta2AR complex, since both antagonists act not only on their own receptor, but also on the reciprocal receptor signalling. The addition of an ACE inhibitor would lower the levels of circulating Ang II and norepinephrine, respectively through inhibition of the renin-angiotensin system and sympathetic nervous system and then cause adverse effects. The lack of significant knowledge of the molecular basis of assembly of the signalling complexes that are targeted by the different drugs is certainly a contributor to these negative effects on general homeostasis. A thorough understanding of the assembly of these receptors, and their partners for regulated cellular localization, is needed to identify the specificity of signal transduction that leads to diseases involving receptors, such as AIDS (CD4, CXCR4 and CCR5), and heart disease (beta2AR, AT1R). Therefore, understanding how the complex interactions between different receptors occur may have important implications for the development of highly specific pharmacological treatments.The function of 7TM-R dimers is still obscure, as are the mechanisms that regulate their dimerization, their association with other signalling partners, and their membrane expression and function in normal tissue and in disease. Chaperones in the endoplasmic reticulum probably associate signalling partners according to their targetting sequences and specific co-translation and transcription of genes. There is now evidence that 7TM-R signalling complexes (composed of receptors, G protein and effectors) form during biosynthesis and are stably assembled before targeting the plasma membrane, yet, very little is known about the chaperones that regulate 7TM-R assembly with its signalling complex. Identification of these chaperones may lead to new therapeutic targets along the intracellular transport of receptors to plasma membrane.