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Regulation of G-protein Coupled Signal Transduction by Scaffolding Proteins

Bih-Hwa Shieh
Department of Pharmacology
402 Medical Research Building I
615-343-0441 (office)

My laboratory is interested in understanding function and regulation of scaffolding proteins in signal transduction. Scaffolding proteins consists of multiple protein-protein interaction motifs and acts by tethering multiple components of a signaling pathway leading to formation of a signal transduction complex. This clustering of signaling molecules may regulate specificity of signaling events. Moreover, it may facilitate protein-protein interaction for fast activation and deactivation of signaling processes. One of the prototypical scaffolding protein is INAD that is essential for visual transduction in Drosophila. Visual transduction is the process that converts the signal of light into a change of membrane potential of photoreceptors. It is a G-protein coupled phospholipase C?-mediated mechanism leading to opening of two cation channels, TRP and TRPL. In the visual cascade, light turns on rhodopsin which activates a Gq. Activated Gq?-subunit switches on a phospholipase C? (NORPA) resulting in breakdown of phospholipids to generate diacylglycerol (DAG) and inositol trisphosphate. DAG is a potent activator of protein kinase C (PKC) that exerts a negative regulation of the visual transduction.

We study how INAD regulates visual transduction. INAD contains five distinct PDZ domains. PDZ domains are protein-protein interaction domains of 90 amino acids in length and are present in many proteins involved in localization and anchoring of signaling molecules. In Drosophila visual cascade, we and others have demonstrated that INAD interacts with three key proteins including the TRP calcium channel, phospholipase C? and eye-PKC. Our current investigation focuses on function of the signaling complex in visual transduction. We employ a combined analysis of molecular biological, biochemical, electrophysiological and genetics methodologies. Insight into how INAD coordinates visual transduction will help gain understanding into regulation of signal transduction by scaffolding proteins.