Many cells express ryanodine receptors (RyRs) whose activation is thought to amplify depolarization-evoked elevations in cytoplasmic Ca2+ concentration ([Ca2+]i) through a process of Ca2+-induced Ca2+ release (CICR). In neurons, it is usually assumed that CICR triggers net Ca2+ release from an ER Ca2+ store. However, since net ER Ca2+ transport depends on the relative rates of Ca2+ uptake and release via distinct pathways, weak activation of a CICR pathway during periods of ER Ca accumulation would have a totally different effect: attenuation of Ca2+ accumulation. Stronger CICR activation at higher [Ca2+]i could further attenuate Ca2+ accumulation or trigger net Ca2+ release, depending on the quantitative properties of the underlying Ca2+ transporters. This and the companion study (Hongpaisan, J., N.B. Pivovarova, S.L. Colgrove, R.D. Leapman, and D.D. Friel, and S.B. Andrews. 2001. J. Gen. Physiol. 118:101–112) investigate which of these CICR “modes” operate during depolarization-induced Ca2+ entry in sympathetic neurons. The present study focuses on small [Ca2+]i elevations (less than ∼350 nM) evoked by weak depolarization. The following two approaches were used: (1) Ca2+ fluxes were estimated from simultaneous measurements of [Ca2+]i and ICa in fura-2–loaded cells (perforated patch conditions), and (2) total ER Ca concentrations ([Ca]ER) were measured using X-ray microanalysis. Flux analysis revealed triggered net Ca2+ release during depolarization in the presence but not the absence of caffeine, and [Ca2+]i responses were accelerated by SERCA inhibitors, implicating ER Ca2+ accumulation, which was confirmed by direct [Ca]ER measurements. Ryanodine abolished caffeine-induced CICR and enhanced depolarization-induced ER Ca2+ accumulation, indicating that activation of the CICR pathway normally attenuates ER Ca2+ accumulation, which is a novel mechanism for accelerating evoked [Ca2+]i responses. Theory shows how such a low gain mode of CICR can operate during weak stimulation and switch to net Ca2+ release at high [Ca2+]i, a transition demonstrated in the companion study. These results emphasize the importance of the relative rates of Ca2+ uptake and release in defining ER contributions to depolarization-induced Ca2+ signals.
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1 July 2001
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June 27 2001
Multiple Modes of Calcium-Induced Calcium Release in Sympathetic Neurons I: Attenuation of Endoplasmic Reticulum Ca2+ Accumulation at Low [Ca2+]i during Weak Depolarization
Meredith A. Albrecht,
Meredith A. Albrecht
aDepartment of Neuroscience, Case Western Reserve University, Cleveland, OH 44106
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Stephen L. Colegrove,
Stephen L. Colegrove
aDepartment of Neuroscience, Case Western Reserve University, Cleveland, OH 44106
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Jarin Hongpaisan,
Jarin Hongpaisan
bLaboratory of Neurobiology, National Institute of Neurological Disorders and Stroke, NIH, Bethesda, MD 20892
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Natalia B. Pivovarova,
Natalia B. Pivovarova
bLaboratory of Neurobiology, National Institute of Neurological Disorders and Stroke, NIH, Bethesda, MD 20892
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S. Brian Andrews,
S. Brian Andrews
bLaboratory of Neurobiology, National Institute of Neurological Disorders and Stroke, NIH, Bethesda, MD 20892
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David D. Friel
David D. Friel
aDepartment of Neuroscience, Case Western Reserve University, Cleveland, OH 44106
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Meredith A. Albrecht
aDepartment of Neuroscience, Case Western Reserve University, Cleveland, OH 44106
Stephen L. Colegrove
aDepartment of Neuroscience, Case Western Reserve University, Cleveland, OH 44106
Jarin Hongpaisan
bLaboratory of Neurobiology, National Institute of Neurological Disorders and Stroke, NIH, Bethesda, MD 20892
Natalia B. Pivovarova
bLaboratory of Neurobiology, National Institute of Neurological Disorders and Stroke, NIH, Bethesda, MD 20892
S. Brian Andrews
bLaboratory of Neurobiology, National Institute of Neurological Disorders and Stroke, NIH, Bethesda, MD 20892
David D. Friel
aDepartment of Neuroscience, Case Western Reserve University, Cleveland, OH 44106
Abbreviations used in this paper: t-BuBHQ, 2,5-di-(t-butyl)-1,4-hydroquinone; EDX, energy-dispersive X-ray; InsP3, d-myo-inositol 1,4,5-trisphosphate; Ryr, ryanodine receptors; SERCA, sarco- and endoplasmic reticulum Ca ATPase; Tg, thapsigargin.
Online ISSN: 1540-7748
Print ISSN: 0022-1295
© 2001 The Rockefeller University Press
2001
The Rockefeller University Press
J Gen Physiol (2001) 118 (1): 83–100.
Citation
Meredith A. Albrecht, Stephen L. Colegrove, Jarin Hongpaisan, Natalia B. Pivovarova, S. Brian Andrews, David D. Friel; Multiple Modes of Calcium-Induced Calcium Release in Sympathetic Neurons I: Attenuation of Endoplasmic Reticulum Ca2+ Accumulation at Low [Ca2+]i during Weak Depolarization. J Gen Physiol 1 July 2001; 118 (1): 83–100. doi: https://doi.org/10.1085/jgp.118.1.83
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