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Role of intracellular calcium stores in hair-cell ribbon synapse

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      Intracellular calcium stores control many neuronal functions such as excitability, gene expression, synaptic plasticity, and synaptic release. Although the existence of calcium stores along with calcium-induced calcium release (CICR) has been demonstrated in conventional and ribbon synapses, functional significance and the cellular mechanisms underlying this role remains unclear. This review summarizes recent experimental evidence identifying contribution of CICR to synaptic transmission and synaptic plasticity in the CNS, retina and inner ear. In addition, the potential role of CICR in the recruitment of vesicles to releasable pools in hair-cell ribbon synapses will be specifically discussed.

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      Most cited references 140

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      Neuronal calcium signaling.

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        NAADP mobilizes calcium from acidic organelles through two-pore channels

        Ca2+ mobilization from intracellular stores represents an important cell signaling process 1 which is regulated, in mammalian cells, by inositol 1,4,5-trisphosphate (InsP3), cyclic ADP ribose (cADPR) and nicotinic acid adenine dinucleotide phosphate (NAADP). InsP3 and cADPR release Ca2+ from sarco / endoplasmic reticulum (S/ER) stores through activation of InsP3 and ryanodine receptors (InsP3Rs and RyRs). By contrast, the nature of the intracellular stores targeted by NAADP and molecular identity of the NAADP receptors remain controversial 1,2, although evidence indicates that NAADP mobilizes Ca2+ from lysosome-related acidic compartments 3,4. Here we show that two-pore channels (TPCs) comprise a family of NAADP receptors, with TPC1 and TPC3 being expressed on endosomal and TPC2 on lysosomal membranes. Membranes enriched with TPC2 exhibit high affinity NAADP binding and TPC2 underpins NAADP-induced Ca2+ release from lysosome-related stores that is subsequently amplified by Ca2+-induced Ca2+ release via InsP3Rs. Responses to NAADP were abolished by disrupting the lysosomal proton gradient and by ablating TPC2 expression, but only attenuated by depleting ER Ca2+ stores or blocking InsP3Rs. Thus, TPCs form NAADP receptors that release Ca2+ from acidic organelles, which can trigger additional Ca2+ signals via S/ER. TPCs therefore provide new insights into the regulation and organization of Ca2+ signals in animal cells and will advance our understanding of the physiological role of NAADP.
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          Ryanodine receptor calcium release channels.

          The ryanodine receptors (RyRs) are a family of Ca2+ release channels found on intracellular Ca2+ storage/release organelles. The RyR channels are ubiquitously expressed in many types of cells and participate in a variety of important Ca2+ signaling phenomena (neurotransmission, secretion, etc.). In striated muscle, the RyR channels represent the primary pathway for Ca2+ release during the excitation-contraction coupling process. In general, the signals that activate the RyR channels are known (e.g., sarcolemmal Ca2+ influx or depolarization), but the specific mechanisms involved are still being debated. The signals that modulate and/or turn off the RyR channels remain ambiguous and the mechanisms involved unclear. Over the last decade, studies of RyR-mediated Ca2+ release have taken many forms and have steadily advanced our knowledge. This robust field, however, is not without controversial ideas and contradictory results. Controversies surrounding the complex Ca2+ regulation of single RyR channels receive particular attention here. In addition, a large body of information is synthesized into a focused perspective of single RyR channel function. The present status of the single RyR channel field and its likely future directions are also discussed.

            Author and article information

            1Department of Otolaryngology, Stanford University School of Medicine Stanford, CA, USA
            2Department of Molecular and Cellular Physiology, Stanford University School of Medicine Stanford, CA, USA
            Author notes

            Edited by: Simona Tritto, Instituto di Ricovero e Cura a Carattere Scientifico C. Mondino, Italy

            Reviewed by: Enrique Soto, Universidad Autónoma de Puebla, Mexico; Francesco Moccia, University of Pavia, Italy

            *Correspondence: Manuel Castellano-Muñoz and Anthony J. Ricci, Department of Otolaryngology, Stanford University School of Medicine, 300 Pasteur Dr. Edwards Building, Room 145, Stanford, CA 94304, USA e-mail: mcastellano@ ; aricci@

            Manuel Castellano-Muñoz and Anthony J. Ricci have contributed equally to this work.

            This article was submitted to the journal Frontiers in Cellular Neuroscience.

            URI :
            Front Cell Neurosci
            Front Cell Neurosci
            Front. Cell. Neurosci.
            Frontiers in Cellular Neuroscience
            Frontiers Media S.A.
            12 June 2014
            : 8
            4054790 10.3389/fncel.2014.00162
            Copyright © 2014 Castellano-Muñoz and Ricci.

            This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

            Figures: 1, Tables: 0, Equations: 0, References: 139, Pages: 10, Words: 0
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            synaptic plasticity, hearing, cicr, calcium store, hair cell, ribbon synapse


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