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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
2R01HL074091-05A2
Application #
7583426
Study Section
Electrical Signaling, Ion Transport, and Arrhythmias Study Section (ESTA)
Program Officer
Przywara, Dennis
Project Start
2009-06-01
Project End
2014-05-31
Budget Start
2009-06-01
Budget End
2010-05-31
Support Year
5
Fiscal Year
2009
Total Cost
$366,250
Indirect Cost
Name
University of Kentucky
Department
Physiology
Type
Schools of Medicine
DUNS #
939017877
City
Lexington
State
KY
Country
United States
Zip Code
40506
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
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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
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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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