Trends in Pharmacological Sciences
The role of the endoplasmic reticulum Ca2+ store in the plasticity of central neurons
Introduction
Synaptic plasticity within hippocampal and cerebellar networks is the probable neural substrate for spatial and motor learning, respectively. Many forms of synaptic plasticity exist; these vary in locus, mechanism and duration of expression but they all depend on Ca2+ as a necessary inductive trigger. In this article, the role of intracellular Ca2+ stores in modulating transmission at hippocampal and cerebellar synapses will be discussed. Ca2+ influx into presynaptic and postsynaptic compartments can be mediated by voltage-gated or neurotransmitter-gated Ca2+ channels in the plasma membrane. Ca2+ influx is driven by a 1000-fold concentration gradient between the extracellular and intracellular spaces {cytosolic [Ca2+] is ∼100 nM}. Ca2+ signals are restricted spatially and temporally by high-capacity Ca2+-binding proteins in the cytosol and transmembrane Ca2+ pumps on the plasma membrane and intracellular organelles. The best characterized of the Ca2+ signalling organelles is the smooth endoplasmic reticulum (SER), a heterogeneous endomembrane system that extends from the neuronal soma to most cell compartments, including axons and dendritic spines [1]. Ca2+ is sequestered into the SER lumen by high-affinity (Km∼1 μM) sarco/endoplasmic reticulum Ca2+-ATPase (SERCA) pumps, which can be inhibited by pharmacological agents such as thapsigargin and cyclopiazonic acid (CPA). Depletion of Ca2+ stores also generates Ca2+ influx via store-operated channels in both axons and dendrites 2, 3, 4. During Ca2+ uptake into the SER, the luminal free [Ca2+] can reach 500 μM, whereas the bound [Ca2+] can be up to three orders of magnitude higher [1]. Even at rest, luminal [Ca2+] can be four times higher than in the cytosol and thus the SER can provide a ready source of Ca2+. The rapid release of Ca2+ from the SER is evoked by stimulation of two largely homologous receptor types on the SER, which are named for their affinity for either the plant alkaloid ryanodine or the cell metabolite inositol (1,4,5)-trisphosphate [Ins(1,4,5)P3].
Section snippets
Receptor pharmacology
Ryanodine receptors have multiple allosteric Ca2+-binding sites responsible for triggering Ca2+-induced Ca2+ release (CICR) from the SER following rises in cytosolic [Ca2+]. In rodent cerebellar tissue, these receptors are maximally responsive to cytosolic [Ca2+] in the 1–10 μM range, and are inhibited by cytosolic [Ca2+] in the low millimolar range [5]. Ins(1,4,5)P3 is a metabolic product of phospholipase C (PLC) activity, which at excitatory synapses is linked to the stimulation of
Receptor localization
Immunohistological techniques have revealed heterogeneous patterns of ryanodine receptor and Ins(1,4,5)P3 receptor expression between and within neuronal cell types. The ryanodine receptor family has three isoforms typically associated with skeletal muscle (RY1), cardiac muscle (RY2) and brain (RY3). However, the RY2 receptor is also present at high density in many neuronal somata, and the RY1 receptor is detected in the cerebellum and, to a lesser extent, in the hippocampus 10, 11. The
Evoked neurotransmitter release and facilitation
Exocytosis of synaptic vesicles at hippocampal synapses can be evoked within 150 μs of a presynaptic action potential (AP) [15], and is dependent on the influx of Ca2+ through voltage-gated Ca2+ channels (VGCCs), which produce a high [Ca2+] at the release site (Figure 1). It is unclear which VGCC subtypes are involved and to what extent CICR contributes to neurotransmitter release. The AP-evoked Ca2+ transient in presynaptic boutons of hippocampal CA3 neurons is depressed by bath application of
Collateral fibre–CA synapses and NMDA receptor-dependent pathways
Long-term potentiation (LTP) at CA3–CA3 and CA3–CA1 collateral synapses in hippocampal slices is induced by asynchronous presynaptic and postsynaptic activity, whereas long-term depression (LTD) is induced by out-of-phase activity [35]. A key feature of both LTP and LTD at collateral synapses is that their induction is blocked by the n-methyl-d-aspartate (NMDA) receptor antagonist d-2-amino-5-phosphonovalerate (APV) [35]. Imaging of individual spines of CA hippocampal neurons has shown that
Neuronal excitability
The excitability of the plasma membrane can be modulated by Ca2+-dependent changes in K+ conductances. These conductances underlie the afterhyperpolarizing potentials (AHPs) that follow bursts of spikes and limit their frequency of neuronal output, and might enhance the temporal precision of EPSP–AP pairings. The early components of the AHP are mediated by big-conductance (BK) and small-conductance (SK) K+ channels [73]. Although SK channel activity is modulated by input to mGlu receptors, the
Concluding remarks
The SER is a dynamic Ca2+ store that is closely coupled to neuronal activity in both presynaptic and postsynaptic neuronal compartments. Although the way in which the SER achieves its diversity of function is not clear, it appears to be essential to the varied behaviour of different synapses. For example, the coupling of the SER to particular VGCC subtypes might determine the contribution of CICR to neurotransmitter release. Similarly, the architecture of the SER at vesicle-release sites might
References (77)
Rapidly exchanging Ca2+ stores in neurons: molecular, structural and functional properties
Prog. Neurobiol.
(2001)Calcium stores in hippocampal synaptic boutons mediate short-term plasticity, store-operated Ca2+ entry, and spontaneous transmitter release
Neuron
(2001)Two types of ryanodine receptors in mouse brain: skeletal muscle type exclusively in Purkinje cells and cardiac muscle type in various neurons
Neuron
(1992)Homer binds a novel proline-rich motif and links group 1 metabotropic glutamate receptors with IP3 receptors
Neuron
(1998)A role for Ca2+ stores in kainate receptor-dependent synaptic facilitation and LTP at mossy fiber synapses in the hippocampus
Neuron
(2003)- et al.
Modulation of presynaptic store calcium induces release of glutamate and postsynaptic firing
Neuron
(2003) - et al.
Definition of the readily releasable pool of vesicles at hippocampal synapses
Neuron
(1996) - et al.
Activity-dependent modulation of the rate at which synaptic vesicles become available to undergo exocytosis
Neuron
(1998) Rapid reuse of readily releasable pool vesicles at hippocampal synapses
Neuron
(2000)- et al.
Selective replenishment of two vesicle pools depends on the source of Ca2+ at the Drosophila synapse
Neuron
(2002)
Single synaptic events evoke NMDA receptor-mediated release of calcium from internal stores in hippocampal dendritic spines
Neuron
Thapsigargin blocks the induction of long-term potentiation in rat hippocampal slices
Neurosci. Lett.
Facilitation of NMDAR-independent LTP and spatial learning in mutant mice lacking ryanodine receptor type 3
Neuron
Two distinct forms of long-term depression coexist in CA1 hippocampal pyramidal cells
Neuron
Long-term potentiation and long-term depression in hippocampal CA1 neurons of mice lacking the IP3 type 1 receptor
Neuroscience
IP3-dependent calcium-induced calcium release mediates bidirectional calcium waves in neurones: functional implications for synaptic plasticity
Biochim. Biophys. Acta
Hippocampal mossy fiber activity evokes Ca2+ release in CA3 pyramidal neurons via a metabotropic glutamate receptor pathway
Neuroscience
Roles of metabotropic glutamate receptors in LTP and LTD in the hippocampus
Curr. Opin. Neurobiol.
Neuronal plasticity in hippocampal mossy fiber–CA3 synapses of mice lacking the inositol-1,4,5-trisphosphate type 1 receptor
Brain Res.
Modified hippocampal long-term potentiation in PKC γ-mutant mice
Cell
Intracellular calcium stores modulate miniature GABA-mediated synaptic currents in neonatal rat hippocampal neurons
Eur. J. Neurosci.
Activity-evoked capacitative Ca2+ entry: implications in synaptic plasticity
J. Neurosci.
Bell-shaped calcium-response curves of Ins(1,4,5)P3- and calcium-gated channels from endoplasmic reticulum of cerebellum
Nature
Identification of a family of calcium sensors as protein ligands of inositol trisphosphate receptor Ca2+ release channels
Proc. Natl. Acad. Sci. U. S. A.
Regulation of InsP3 receptor activity by neuronal Ca2+-binding proteins
EMBO J.
Ryanodine receptor calcium release channels
Physiol. Rev.
Pharmacology of inositol trisphosphate receptors
Pflugers Arch.
Spatial learning induced changes in expression of the ryanodine type II receptor in the rat hippocampus
FASEB J.
Differential cellular expression of isoforms of inositol 1,4,5-triphosphate receptors in neurons and glia in brain
J. Comp. Neurol.
Differential immunohistochemical localization of inositol 1,4,5-trisphosphate- and ryanodine-sensitive Ca2+ release channels in rat brain
J. Neurosci.
Timing of neurotransmission at fast synapses in the mammalian brain
Nature
Presynaptic ryanodine-sensitive calcium stores contribute to evoked neurotransmitter release at the basket cell–Purkinje cell synapse
J. Neurosci.
Assessing the role of calcium-induced calcium release in short-term presynaptic plasticity at excitatory central synapses
J. Neurosci.
The contribution of intracellular calcium stores to mEPSCs recorded in layer II neurones of rat barrel cortex
J. Physiol.
Presynaptic calcium stores underlie large-amplitude miniature IPSCs and spontaneous calcium transients
Nat. Neurosci.
Presynaptic internal Ca2+ stores contribute to inhibitory neurotransmitter release onto mouse cerebellar Purkinje cells
Br. J. Pharmacol.
A Ca2+-induced Ca2+ release mechanism involved in asynchronous exocytosis at frog motor nerve terminals
J. Gen. Physiol.
Properties of carbachol-induced oscillatory activity in rat hippocampus
J. Neurophysiol.
Cited by (162)
Ryanodine receptor-dependent mechanisms of PCB developmental neurotoxicity
2023, Advances in Neurotoxicology