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Controlling G protein signaling In Vivo
We have recently published a review in Trends in Pharmacological Sciences describing the design, testing, and use of RASSLs: Scearce-Levie et al, (2001) Engineering Receptors Activated Solely by Synthetic Ligands (RASSLs). Trends Pharmacol. Sci. 22:414–420.
Below is a general discussion of RASSL development.
Research in the Conklin Lab is focused on the molecular basis of signaling by G protein-coupled receptors. We use genetic engineering techniques to create new G proteins and receptors in order to identify the functional domains of these signaling molecules (1) and redirect hormonal signals (2) . Our primary project is to develop new receptors that can be used as molecular "switches" to regulate growth and secretion in transfected cells and transgenic mice.
G protein signaling plays a crucial role in many physiologic processes that are best studied in vivo, such as cell proliferation, hormone secretion, neurotransmission, heart rate control, and smooth muscle contraction. Current studies of these physiologic processes are limited by the fact that we lack control over the effects of endogenous hormones and hormone receptors. To control receptor signaling we are engineering G protein-coupled receptors in an effort to make them respond exclusively to the drug (synthetic small molecule ligand), but not to the natural ligand. These receptors are designated RASSLs, an acronym for "Receptor Activated Solely by a Synthetic Ligand." We are particularly interested in using a RASSL to control hepatic and hematopoietic proliferation since we would like to induce a proliferative amplification of cells that have been genetically modified for the purposes of gene therapy, or tissue engineering.
G protein-coupled receptors form a large family of evolutionarily related proteins. The natural ligands for G protein-coupled receptors are either peptides or smaller non-protein molecules. The binding sites for peptides tend to be in the extracellular loops of the receptor, while those for small molecules tend to be in the transmembrane domains of the receptor (3) (see Fig. 1A). Presumably, the transmembrane domain binding sites are only accessible to the small molecule drugs while the extracellular loops can accommodate binding by larger molecules such as peptides. Many peptide-activated G protein-coupled receptors can also be activated by small molecule drugs (Fig.1A). This offers the opportunity to mutate peptide receptors in ways that selectively inhibit the binding of peptides while maintaining high-affinity binding of synthetic drugs (see Fig.1B).