Regulation and Dysregulation of Cardiac EC coupling by Calmodulin

Ohio State University, Columbus OH

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Abstract

Abstract The small Ca binding protein, calmodulin (CaM), either directly controls, or at minimum, modulates every functionality within the heart. This versatile and ubiquitous Ca binding protein is the only known exception to the central rule of biology - one gene one protein. In all mammalian cells, an identical CaM protein is derived from three different genes, CaM1,2 and 3. Finding the reason for this deviation is not only important to explain this biological conundrum, but for understanding the vast signaling processes mediated by CaM in various cell types including cardiac myocytes in health and disease. CaM is known to bind and regulate hundreds of target proteins. Due to the fact that the free concentration of CaM is limited within cardiac myocytes, yet the bound protein is abundant, we surmise the presence of the three different genes is important for orchestrating specific and unique myocyte CaM-mediated Ca signaling processes in space and time. We propose the divergent 5’ and 3’ UTRs of the three CaM genes recruit different RNA binding proteins used to transport and pool together specific CaM target proteins’ mRNAs into discrete “interactosomes”. We hypothesize these mRNA clusters are then locally translated together (“tranlatosomes”) where the proteins function within the cardiac myocyte and are thus “functionally distributed”. We have created novel imaging tools and data analysis software in order to visualize these processes. We have also discovered in the adult cardiac myocyte that ribosomal translocons, rough ER, and the golgi complex actively process and translate transmembrane proteins far from the perinuclear space, contradictory to the long held classical view of membrane protein translation. In this proposal, we will define the abundance, subcellular distribution, sites of translation and physiological modulation for the three CaM mRNAs, along with key CaM targets in cardiac myocytes in health and disease. Ultimately, we will apply this novel and new knowledge to target our therapeutically engineered proteins with high precision and specificity to select “interactosomes” in order to treat various cardiovascular diseases.