| Popis: |
G protein-coupled receptors (GPCRs) are plasma membrane proteins that act as sensors for extracellular stimuli (e.g., photons, neurohumoral moduluators, odorants and tastants, lipids). The cognate stimulus for a GPCR induces a conformational change that catalyzes, via heterotrimeric G proteins, a series of biochemical reactions inside the cell (i.e., a response); the responses can lead to phenomena such as differentiation, morphological changes, chemotaxis, and mitosis. G protein-coupled receptors are the targets of, in addition to endogenous neurohumoral molecules, more than 30% of currently marketed pharmaceutical drugs. For instance, the effective appetite suppressant fenfluramine reduces appetite via activation of serotonin (5-hydroxytryptamine, 5-HT) 2C (5-HT2C) receptors. Fenfluramine was, despite its efficacy as an anorexigen, withdrawn from market due to its association with life-threatening cardiovascular side effects [i.e., valvular heart disease (VHD) and pulmonary hypertension (PH)]. The work presented in this thesis describes efforts to identify the cellular and molecular mechanisms responsible for fenfluramine-induced VHD. Evidence is presented that both fenfluramine and, to a greater extent, its major in vivo metabolite norfenfluramine, activate mitogenic 5-HT2B receptors, which are expressed in human heart valve interstitial cells (VICs). Both fenfluramine and norfenfluramine induce mitogenic responses from VICs in vitro that are abrogated by a 5-HT2B receptor antagonist. Further, data implicating van der Waals’ (vdW) interactions between the α-methyl group of S-(+)-norfenfluramine and a valine in the second transmembrane helix of the receptor (V2.53) in the compound’s valvulopathic—but not anorexigenic—effects are described. The implication of the findings described herein on preventing drug-associated cardiopulmonary side effects and developing safe, effective anorexigens are also discussed. |
