Abstract
Darier's disease (DD) is a high penetrance, autosomal dominant mutation in the ATP2A2 gene, which encodes the SERCA2 Ca2+ pump. Here we have used a mouse model of DD, a SERCA2(+/-) mouse, to define the adaptation of Ca2+ signaling and Ca2+-dependent exocytosis to a deletion of one copy of the SERCA2 gene. The [Ca2+]i transient evoked by maximal agonist stimulation was shorter in cells from SERCA2(+/-) mice, due to an up-regulation of specific plasma membrane Ca2+ pump isoforms. The change in cellular Ca2+ handling caused approximately 50% reduction in [Ca2+]i oscillation frequency. Nonetheless, agonist-stimulated exocytosis was identical in cells from wild-type and SERCA2(+/-) mice. This was due to adaptation in the levels of the Ca2+ sensors for exocytosis synaptotagmins I and III in cells from SERCA2(+/-) mice. Accordingly, exocytosis was approximately 10-fold more sensitive to Ca2+ in cells from SERCA2(+/-) mice. These findings reveal a remarkable plasticity and adaptability of Ca2+ signaling and Ca2+-dependent cellular functions in vivo, and can explain the normal function of most physiological systems in DD patients.
Publication types
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Brain / enzymology*
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Calcium / metabolism*
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Calcium Signaling / physiology*
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Calcium-Transporting ATPases / deficiency
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Calcium-Transporting ATPases / genetics*
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Calcium-Transporting ATPases / metabolism*
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Carbachol / pharmacology
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Cell Membrane Permeability
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Darier Disease / genetics
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Exocytosis / physiology*
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Gene Expression Regulation, Enzymologic / drug effects
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Heterozygote
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Humans
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In Vitro Techniques
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Isoenzymes / genetics
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Isoenzymes / metabolism
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Large-Conductance Calcium-Activated Potassium Channels
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Mice
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Mice, Knockout
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Mutation
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Pancreas / enzymology
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Pancreas / physiology*
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Potassium Channels / physiology
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Potassium Channels, Calcium-Activated*
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RNA, Messenger / genetics
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Reverse Transcriptase Polymerase Chain Reaction
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Sarcoplasmic Reticulum Calcium-Transporting ATPases
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Transcription, Genetic / drug effects
Substances
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Isoenzymes
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Large-Conductance Calcium-Activated Potassium Channels
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Potassium Channels
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Potassium Channels, Calcium-Activated
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RNA, Messenger
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Carbachol
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Sarcoplasmic Reticulum Calcium-Transporting ATPases
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ATP2A2 protein, human
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Atp2a2 protein, mouse
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Calcium-Transporting ATPases
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Calcium