title: Interplay between ER Ca2+ uptake and release fluxes in neurons and its impact on [Ca2+] dynamics.
abstract: In neurons, depolarizing stimuli open voltage-gated Ca2+ channels, leading to Ca2+ entry and a rise in the cytoplasmic free Ca2+ concentration ([Ca2+]i). While such [Ca2+]i elevations are initiated by Ca2+ entry, they are also influenced by Ca2+ transporting organelles such as mitochondria and the endoplasmic reticulum (ER). This review summarizes contributions from the ER to depolarization-evoked [Ca2+]i responses in sympathetic neurons. As in other neurons, ER Ca2+ uptake depends on SERCAs, while passive Ca2+ release depends on ryanodine receptors (RyRs). RyRs are Ca2+ permeable channels that open in response to increases in [Ca2+]i, thereby permitting [Ca2+]i elevations to trigger Ca2+ release through Ca(2+)-induced Ca2+ release (CICR). However, whether this leads to net Ca2+ release from the ER critically depends upon the relative rates of Ca2+ uptake and release. We found that when RyRs are sensitized with caffeine, small evoked [Ca2+]i elevations do trigger net Ca2+ release, but in the absence of caffeine, net Ca2+ uptake occurs, indicating that Ca2+ uptake is stronger than Ca2+ release under these conditions. Nevertheless, by increasing ER Ca2+ permeability, RyRs reduce the strength of Ca2+ buffering by the ER in a [Ca2+](I)-dependent manner, providing a novel mechanism for [Ca2+]i response acceleration. Analysis of the underlying Ca2+ fluxes provides an explanation of this and two other modes of CICR that are revealed as [Ca2+]i elevations become progressively larger.
authors.affiliation: Dept. of Neurosciences, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA. ddf2@po.cwru.edu
authors.forename: David
authors.initials: D
authors.lastname: Friel
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D015220:Calcium Channels / Q000378:metabolism / Q000502:physiology*; D020013:Calcium Signaling / Q000502:physiology*; D003600:Cytosol / Q000378:metabolism / Q000502:physiology; D004594:Electrophysiology; D004721:Endoplasmic Reticulum / Q000378:metabolism / Q000502:physiology*; D015544:Inositol 1,4,5-Trisphosphate / Q000502:physiology; D008564:Membrane Potentials / Q000502:physiology; D009474:Neurons / Q000378:metabolism / Q000502:physiology*; D019837:Ryanodine Receptor Calcium Release Channel / Q000378:metabolism / Q000502:physiology*
chemical_list: D015220:Calcium Channels; D019837:Ryanodine Receptor Calcium Release Channel; D015544:Inositol 1,4,5-Trisphosphate; D002118:Calcium