Ca dysregulation in cardiac myocytes contributes to heart development defects and diseases of the aging heart. The long-term objective of this proposal is to provide a molecular mechanism that explains how cardiac L-type Ca channels (LTCC) sense and transduce signals that homeostatically regulate cardiac myocytes. Cardiac myocytes present a conundrum with respect to Ca signaling to the nucleus. Cytosolic Ca amplitude varies >10-fold during each cardiac cycle, yet alterations of Ca somehow are differentially decoded for longer-term transcriptional signaling. In this funding period we will test whether Ca channel activity and the cardiac L-type Ca channel itself encodes Ca signaling for long-term regulation. In the past funding period we discovered that RGK chronically inhibited ICa,L (LTCC current), and this RGK inhibition of ICa,L resulted in a compensatory up-regulation of CaV1.2 mRNA. This suggests that ICa,L block may signal transcriptional events in the nucleus. In new studies we confirmed and extended this notion by showing that LTCC-pharmacological- block, but not internal Ca in general is responsible for perturbing heart development. Along the same lines, in mature heart, long-term blockade of LTCC also causes a compensatory up-regulation of LTCC and ICa,L. Our driving hypothesis is that signaling is not simply determined by Ca, but by active Ca channels. The discovery that mobile segment of LTCC is localized to the nucleus or t-tubules coupled with the recent report that this peptide is a transcription factor drives the exciting new hypothesis that this segment of the LTCC, regulates LTCC expression. We will study this aspect of long-term channel regulation in three aims: 1. We will assess nuclear translocation of a domain of the LTCC, and determine the interaction between LTCC activity and sub- cellular localization;2. We will determine the ability of LTCC to auto-regulate itself transcriptionally;and 3. We will determine the compensatory changes of SL Ca handling proteins in response to LTCC blockade. This work may provide a missing molecular link between LTCC function and downstream signaling events.
These studies show that widely used clinically-relevant drugs that are used to block LTCC may inadvertently exacerbate heart dysfunction by paradoxically increasing LTCC function. This proposal will lead to understanding of a new mechanism whereby ion channels that control cardiac electrical activity also may control long-term signaling pathways that are critical for maintenance of cardiac structure and function.
| Manning, Janet R; Chelvarajan, Lakshman; Levitan, Bryana M et al. (2018) Rad GTPase deletion attenuates post-ischemic cardiac dysfunction and remodeling. JACC Basic Transl Sci 3:83-96 |
| Levitan, Bryana M; Manning, Janet R; Withers, Catherine N et al. (2016) Rad-deletion Phenocopies Tonic Sympathetic Stimulation of the Heart. J Cardiovasc Transl Res 9:432-444 |
| Manning, Janet R; Withers, Catherine N; Levitan, Bryana et al. (2015) Loss of Rad-GTPase produces a novel adaptive cardiac phenotype resistant to systolic decline with aging. Am J Physiol Heart Circ Physiol 309:H1336-45 |
| Yin, Guo; Hassan, Faisal; Haroun, Ayman R et al. (2014) Arrhythmogenic calmodulin mutations disrupt intracellular cardiomyocyte Ca2+ regulation by distinct mechanisms. J Am Heart Assoc 3:e000996 |
| Kiper, Carmen; Grimes, Barry; Van Zant, Gary et al. (2013) Mouse strain determines cardiac growth potential. PLoS One 8:e70512 |
| Manning, Janet R; Yin, Guo; Kaminski, Catherine N et al. (2013) Rad GTPase deletion increases L-type calcium channel current leading to increased cardiac contraction. J Am Heart Assoc 2:e000459 |
| Crump, Shawn M; Andres, Douglas A; Sievert, Gail et al. (2013) The cardiac L-type calcium channel distal carboxy terminus autoinhibition is regulated by calcium. Am J Physiol Heart Circ Physiol 304:H455-64 |
| Gunton, Jenny E; Sisavanh, Mary; Stokes, Rebecca A et al. (2012) Mice deficient in GEM GTPase show abnormal glucose homeostasis due to defects in beta-cell calcium handling. PLoS One 7:e39462 |
| Magyar, J; Jenes, A; Kistamás, K et al. (2011) Long term regulation of cardiac L-type calcium channel by small G proteins. Curr Med Chem 18:3714-9 |
| Satin, Jonathan; Schroder, Elizabeth A; Crump, Shawn M (2011) L-type calcium channel auto-regulation of transcription. Cell Calcium 49:306-13 |
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