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.
|Kiper, Carmen; Grimes, Barry; Van Zant, Gary et al. (2013) Mouse strain determines cardiac growth potential. PLoS One 8:e70512|
|Satin, Jonathan; Schroder, Elizabeth A; Crump, Shawn M (2011) L-type calcium channel auto-regulation of transcription. Cell Calcium 49:306-13|
|Schroder, Elizabeth; Byse, Miranda; Satin, Jonathan (2009) L-type calcium channel C terminus autoregulates transcription. Circ Res 104:1373-81|
|Satin, Jonathan; Schroder, Elizabeth A (2009) Autoregulation of cardiac l-type calcium channels. Trends Cardiovasc Med 19:268-71|
|Lester, William C; Schroder, Elizabeth A; Burgess, Don E et al. (2008) Steady-state coupling of plasma membrane calcium entry to extrusion revealed by novel L-type calcium channel block. Cell Calcium :|
|Correll, Robert N; Pang, Chunyan; Finlin, Brian S et al. (2007) Plasma membrane targeting is essential for Rem-mediated Ca2+ channel inhibition. J Biol Chem 282:28431-40|
|Schroder, Elizabeth; Magyar, Janos; Burgess, Don et al. (2007) Chronic verapamil treatment remodels ICa,L in mouse ventricle. Am J Physiol Heart Circ Physiol 292:H1906-16|
|Finlin, Brian S; Correll, Robert N; Pang, Chunyan et al. (2006) Analysis of the complex between Ca2+ channel beta-subunit and the Rem GTPase. J Biol Chem 281:23557-66|
|Crump, Shawn M; Correll, Robert N; Schroder, Elizabeth A et al. (2006) L-type calcium channel alpha-subunit and protein kinase inhibitors modulate Rem-mediated regulation of current. Am J Physiol Heart Circ Physiol 291:H1959-71|
|Schroder, Elizabeth A; Wei, Yidong; Satin, Jonathan (2006) The developing cardiac myocyte: maturation of excitability and excitation-contraction coupling. Ann N Y Acad Sci 1080:63-75|
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