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Molecular basis for the modulation of native T-type Ca2+ channels in vivo by Ca2+ /calmodulin-dependent protein kinase II
Junlan Yao, … , Roger J. Colbran, Paula Q. Barrett
Junlan Yao, … , Roger J. Colbran, Paula Q. Barrett
Published September 1, 2006
Citation Information: J Clin Invest. 2006;116(9):2403-2412. https://doi.org/10.1172/JCI27918.
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Research Article Cardiology

Molecular basis for the modulation of native T-type Ca2+ channels in vivo by Ca2+ /calmodulin-dependent protein kinase II

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Abstract

Ang II receptor activation increases cytosolic Ca2+ levels to enhance the synthesis and secretion of aldosterone, a recently identified early pathogenic stimulus that adversely influences cardiovascular homeostasis. Ca2+/calmodulin-dependent protein kinase II (CaMKII) is a downstream effector of the Ang II–elicited signaling cascade that serves as a key intracellular Ca2+ sensor to feedback-regulate Ca2+ entry through voltage-gated Ca2+ channels. However, the molecular mechanism(s) by which CaMKII regulates these important physiological targets to increase Ca2+ entry remain unresolved. We show here that CaMKII forms a signaling complex with α1H T-type Ca2+ channels, directly interacting with the intracellular loop connecting domains II and III of the channel pore (II-III loop). Activation of the kinase mediated the phosphorylation of Ser1198 in the II-III loop and the positive feedback regulation of channel gating both in intact cells in situ and in cells of the native adrenal zona glomerulosa stimulated by Ang II in vivo. These data define the molecular basis for the in vivo modulation of native T-type Ca2+ channels by CaMKII and suggest that the disruption of this signaling complex in the zona glomerulosa may provide a new therapeutic approach to limit aldosterone production and cardiovascular disease progression.

Authors

Junlan Yao, Lucinda A. Davies, Jason D. Howard, Scott K. Adney, Philip J. Welsby, Nancy Howell, Robert M. Carey, Roger J. Colbran, Paula Q. Barrett

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Figure 6

Phosphorylation-state of Ser1198 in α1H channels in situ and in vivo.

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                  Phosphorylation-state of Ser1198 in α1H
             ...
Immunohistochemical detection of pS1198 in: CaMKIIγC-transfected α1H/mTREK double-stable cells following 6 mM K+ depolarization (1 minute) (A); thin sections of rat adrenal glands harvested 30 minutes after vehicle or Ang II infusion, 50–200 ng/kg/min (n = 4 and 7 animals, respectively) (B); thin sections of rat adrenal glands subcapsularly perfused (1 μl/min) with D5W with or without 100 μM KN-93 30 minutes before and during a 30-minute systemic infusion of Ang II at 50 ng/kg/min in uniadrenalectomized rats (n = 3 animals each) (C). Anti-RAEpS1198 immunohistochemistry revealed DAB immunostaining in the subcapsular ZG (B and C). Note the increase in signal strength after stimulation (A–C). Signal competed with an 80-fold molar excess of antigenic phosphopeptide, pS1198 peptide, but not non-phosphopeptide, S1198 peptide, evaluated at either ×40 (B, bottom row; and C) or ×100 (B, top row; and A). All samples were counterstained with hematoxylin. Quantification of ZG DAB immunostaining expressed as percent of ROI. #P < 0.05, control S1198 peptide versus antibody alone. ##P < 0.05, stimulated pS1198 peptide versus antibody alone (ANOVA on ranks, Student-Newman-Keuls method). †P < 0.05, KN-93 versus vehicle, infused using the primary antibody alone or with pS1198 peptide preadsorption (ANOVA, Student-Newman-Keuls method).

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ISSN: 0021-9738 (print), 1558-8238 (online)

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