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- Title
Molecular basis for the modulation of native T-type Ca2+ channels in vivo by Ca2+/calmodulin-dependent protein kinase II.
- Authors
Yao, Junlan; Davies, Lucinda A; Howard, Jason D; Adney, Scott K; Welsby, Philip J; Howell, Nancy; Carey, Robert M; Colbran, Roger J; Barrett, Paula Q
- 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 alpha1H 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.
- Subjects
BIOCHEMISTRY; CALCIUM; CELL lines; CELLULAR signal transduction; COMPARATIVE studies; DNA probes; DOCUMENTATION; GENETIC techniques; KIDNEYS; PHENOMENOLOGY; RESEARCH methodology; MEDICAL cooperation; NUCLEOTIDES; PHOSPHORYLATION; PHOSPHOTRANSFERASES; RECOMBINANT proteins; RESEARCH; EVALUATION research
- Publication
Journal of Clinical Investigation, 2006, Vol 116, Issue 9, p2403
- ISSN
0021-9738
- Publication type
journal article