Voltage-activated Ca channels serve two critical functions: the regulation of cellular excitability and the regulation of Ca entry. Alterations in the density, or function, of L-type Ca channels are implicated in a variety of cardiovascular diseases. Thus, elaborating the basic mechanisms that regulate Ca channels is important for understanding both fundamental channel physiology and for therapeutic intervention. During the past funding period, we have identified the Rem GTPase as a novel modulator of I(Ca). It was originally thought that Rem association with CaVbeta- subunits chronically regulated I(Ca) by inhibiting channel trafficking. Our studies have disproved this hypothesis, demonstrating Rem-mediated Ca channel regulation without changes in surface density. Instead, Rem seems to modulate Ca channel activity through interactions with both CaVbeta and the proximal CaV1.2 C-terminus near the CB/IQ domain. Two of the most physiologically relevant controls of I(Ca) are PKA-modulation and calmodulin (CaM)-modulation. Our most recent studies suggest that Rem modulates I(Ca) responses to each of these signaling pathways. Thus, Rem appears to contribute to both beta-adrenergic and Ca-CaM control of I(Ca). The specific hypothesis to be tested is that Rem GTPase regulates Ca channel activity in cardiac muscle through interactions with both CaVb-subunits and the CaV1.2 C- terminus. Three hypothesis driven aims focus our studies and advance knowledge of this novel regulatory mechanism.
Aim 1 will explore the nature of Rem-mediated channel regulation by examining the effect of Rem loss on Ca channel regulation. Initial characterization of Rem knockout mice indicates that i) Rem functions in vivo to regulate I(Ca);ii) contributes to the cardiac response to pressure-overload;and iii) contributes to cardiac myocyte growth/maturation homeostasis.
Aim 2 will determine whether interaction of Rem with CaVbeta or CB/IQ is critical for modulation of I(Ca).
Aim 3 will investigate how Ca- calmodulin modulates Rem-mediated channel blockade, and determine whether PKA phosphorylation alters Rem membrane trafficking or the interaction between Rem and its binding partners. RGK G-proteins function as modulators of Ca channel activity, contributing to regulation of I(Ca), excitation- contraction coupling, and the cardiac response to pressure-overload. The goal of this research is to generate a deeper understanding of the physiological ramifications and molecular mechanism of RGK/Ca channel modulation, to speed progress toward the therapeutic exploitation of RGKs in cardiovascular disease.

Public Health Relevance

Voltage-activated calcium channels serve two critical functions: the regulation of calcium entry and the control of heart contraction. Changes in the number, or function, of L-type calcium channels are implicated in a variety of cardiovascular disease, including atrial fibrillation, heart failure, and ischemic heart disease. Thus, understanding the basic mechanisms that regulate calcium cannels is important in understanding both fundamental heart muscle performance and for therapeutic intervention. We have identified a family of proteins that regulate calcium channels and the goal of this research is to speed progress toward the day when these proteins can be used to treat heart disease.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Electrical Signaling, Ion Transport, and Arrhythmias Study Section (ESTA)
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Krull, Holly
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University of Kentucky
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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
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 44:353-62
Correll, Robert N; Botzet, Gregory J; Satin, Jonathan et al. (2008) Analysis of the Rem2 - voltage dependant calcium channel beta subunit interaction and Rem2 interaction with phosphorylated phosphatidylinositide lipids. Cell Signal 20:400-8
Correll, Robert N; Pang, Chunyan; Niedowicz, Dana M et al. (2008) Calmodulin binding is dispensable for Rem-mediated Ca2+ channel inhibition. Mol Cell Biochem 310:103-10
Correll, Robert N; Pang, Chunyan; Niedowicz, Dana M et al. (2008) The RGK family of GTP-binding proteins: regulators of voltage-dependent calcium channels and cytoskeleton remodeling. Cell Signal 20:292-300
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
Andres, Douglas A; Crump, Shawn M; Correll, Robert N et al. (2006) Analyses of Rem/RGK signaling and biological activity. Methods Enzymol 407:484-98
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
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

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