Ca2+ and the regulation of neurotransmitter secretion

doi:10.1016/S0959-4388(97)80058-X

Current Opinion in Neurobiology

Volume 7, Issue 3, June 1997, Pages 316-322

https://doi.org/10.1016/S0959-4388(97)80058-X Get rights and content

Abstract

Ca²⁺ plays an important role in the regulation of multiple steps that contribute to neurotransmitter secretion. Electrophysiological approaches have defined the nature of the Ca²⁺ signal and its sites of action, while recent biochemical, molecular, and genetic approaches have identified and characterized candidate molecular targets for Ca²⁺ regulation.

References (69)

SM Bajjalieh et al.
The biochemistry or neurotransmitter secretion
J Biol Chem
(1995)
RS Zucker
Exocytosis: a molecular and physiological perspective
Neuron
(1996)
S Mennerick et al.
Ultrafast exocytosis elicited by calcium current in synaptic terminals of retinal bipolar neurons
Neuron
(1996)
JH Koenig et al.
Calcium-induced translocation of synaptic vesicles to the active site
J Neurosci
(1993)
Y Goda et al.
Two components of transmitter release at a central synapse
Proc Natl Acad Sci USA
(1994)
RD Burgoyne et al.
Ca²⁺ and secretory-vesicle dynamics
Trends Neurosci
(1995)
TF Martin et al.
Late ATP-dependent and Ca⁺⁺-activated steps of dense core granule exocytosis
Cold Spring Harb Symp Quant Biol
(1995)
TC Südhof et al.
Synaptotagmins: C2-domain proteins that regulate membrane traffic
Neuron
(1996)
K Broadie et al.
Absence of synaptotagmin disrupts excitation-secretion coupling during synaptic transmission
Proc Natl Acad Sci USA
(1994)
RB Sutton et al.
Structure of the first C2 domain of synaptotagmin I: a novel Ca²⁺/phospholipid-binding fold
Cell
(1995)

C Li et al.

Ca²⁺-dependent and -independent activities of neural and non-neural synaptotagmins

Nature

(1995)

ER Chapman et al.

A novel function for the second C2 domain of synaptotagmin. Ca²⁺-triggered dimerization

J Biol Chem

(1996)

R Heidelberger et al.

Calcium dependence of the rate of exocytosis in a synaptic terminal

Nature

(1994)

BA Davletov et al.

Ca²⁺-dependent conformational change in synaptotagmin I

J Biol Chem

(1994)

C Li et al.

Distinct Ca²⁺ andSr²⁺ binding properties of synaptotagmins. Definition of candidate Ca²⁺ sensors for the fast and slow components of neurotransmitter release

J Biol Chem

(1995)

T Yamaguchi et al.

Two functionally different domains of rabphilin-3A, Rab3A p25/smg p25A-binding and phospholipid- and Ca²⁺-binding domains

J Biol Chem

(1993)

S Orita et al.

Doc2 enhances Ca²⁺-dependent exocytosis from PC12 cells

J Biol Chem

(1996)

S Ahmed et al.

The Caenorhabditis elegans unc-13 gene product is a phospholipid-dependent high-affinity phorbol ester receptor

Biochem J

(1992)

A Betz et al.

Direct interaction of the rat unc-13 homologue munc13-1 with the N terminus of syntaxin

J Biol Chem

(1997)

ZH Sheng et al.

Identification of a syntaxin-binding site on N-type calcium channels

Neuron

(1994)

J Rettig et al.

Isoform-specific interaction of the α1A subunits of brain Ca²⁺ channels with the presynaptic proteins syntaxin and SNAP-25

Proc Natl Acad Sci USA

(1996)

ZH Sheng et al.

Calcium-dependent interaction of N-type calcium channels with the synaptic core complex

Nature

(1996)

S Mochida et al.

Inhibition of neurotransmission by peptides containing the synaptic protein interaction site of N-type Ca²⁺ channels.

Neuron

(1996)

I Bezprozvanny et al.

Functional impact of syntaxin on gating of N-type and Q-type calcium channels

Nature

(1995)

JC Hay et al.

Resolution of regulated secretion into sequential MgATP-dependent and calcium-dependent stages mediated by distinct cytosolic proteins

J Cell Biol

(1992)

PA Janmey

Phosphoinositides and calcium as regulators of cellular actin assembly and disassembly

Annu Rev Physiol

(1994)

J-M Trifaró et al.

Cytoskeleton dynamics during neurotransmitter release

Trends Neurosci

(1993)

P Greengard et al.

Synaptic vesicle phosphoproteins and the regulation of synaptic function

Science

(1993)

G Schiavo et al.

A possible docking and fusion particle for synaptic transmission

Nature

(1995)

TC Südhof

The synaptic vesicle cycle: a cascade of protein-protein interactions

Nature

(1995)

N Calakos et al.

Synaptic vesicle biogenesis, docking, and fusion: a molecular description

Physiol Rev

(1996)

SF Hsu et al.

Adaptation of Ca²⁺-triggered exocytosis in presynaptic terminals

Neuron

(1996)

C Rosenmund et al.

Definition of the readily releasable pool of vesicles at hippocampal synapses

Neuron

(1996)

MA Bittner et al.

Kinetic analysis of secretion from permeabilized adrenal chromaffin cells reveals distinct components

J Biol Chem

(1992)

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Citation Excerpt :
Ca2+ signaling plays a pivotal role in regulating various cellular responses, including cell metabolism, cytoskeletal dynamics, the cell cycle, gene expression, neurotransmission, and intracellular signal transduction processes (1, 2).
The U-box E3 ubiquitin ligase CHIP (C terminus of Hsc70-interacting protein) binds Hsp90 and/or Hsp70 via its tetratricopeptide repeat (TPR), facilitating ubiquitination of the chaperone-bound client proteins. Mechanisms that regulate the activity of CHIP are, at present, poorly understood. We previously reported that Ca²⁺/S100 proteins directly associate with the TPR proteins, such as Hsp70/Hsp90-organizing protein (Hop), kinesin light chain, Tom70, FKBP52, CyP40, and protein phosphatase 5 (PP5), leading to the dissociation of the interactions of the TPR proteins with their target proteins. Therefore, we have hypothesized that Ca²⁺/S100 proteins can interact with CHIP and regulate its function. GST pulldown assays indicated that Ca²⁺/S100A2 and S100P bind to the TPR domain and lead to interference with the interactions of CHIP with Hsp70, Hsp90, HSF1, and Smad1. In vitro ubiquitination assays indicated that Ca²⁺/S100A2 and S100P are efficient and specific inhibitors of CHIP-mediated ubiquitination of Hsp70, Hsp90, HSF1, and Smad1. Overexpression of S100A2 and S100P suppressed CHIP-chaperone complex-dependent mutant p53 ubiquitination and degradation in Hep3B cells. The association of the S100 proteins with CHIP provides a Ca²⁺-dependent regulatory mechanism for the ubiquitination and degradation of intracellular proteins by the CHIP-proteasome pathway.
Background: CHIP is a U-box E3 ubiquitin ligase that facilitates the proteasomal degradation of many client proteins.
Results: Ca²⁺/S100 proteins directly interact with CHIP and suppress the ubiquitination and degradation of the client proteins.
Conclusion: We have identified S100 proteins as novel Ca²⁺-dependent regulators of the CHIP-proteasome pathway.
Significance: This is the first indication that S100 proteins form a link between Ca²⁺ signal transduction and the CHIP-proteasome pathway.
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Citation Excerpt :
Whether CART induces c-Fos expression in the venom gland remains to be seen. Ca2+ plays a pivotal role in regulating cellular responses including cell metabolism, muscle contraction, secretion, cell cycle progression, gene expression, neurotransmission, and intracellular signal transduction [43]. These actions depend on a host of Ca2+-binding proteins [44].
Thalassophryne nattereri (niquim) is a venomous fish found on the northern and northeastern coasts of Brazil. Every year, hundreds of humans are affected by the poison, which causes excruciating local pain, edema, and necrosis, and can lead to permanent disabilities. In experimental models, T. nattereri venom induces edema and nociception, which are correlated to human symptoms and dependent on venom kininogenase activity; myotoxicity; impairment of blood flow; platelet lysis and cytotoxicity on endothelial cells. These effects were observed with minute amounts of venom. To characterize the primary structure of T. nattereri venom toxins, a list of transcripts within the venom gland was made using the expressed sequence tag (EST) strategy. Here we report the analysis of 775 ESTs that were obtained from a directional cDNA library of T. nattereri venom gland. Of these ESTs, 527 (68%) were related to sequences previously described. These were categorized into 10 groups according to their biological functions. Sequences involved in gene and protein expression accounted for 14.3% of the ESTs, reflecting the important role of protein synthesis in this gland. Other groups included proteins engaged in the assembly of disulfide bonds (0.5%), chaperones involved in the folding of nascent proteins (1.4%), and sequences related to clusterin (1.5%), as well as transcripts related to calcium binding proteins (1.0%). We detected a large cluster (1.3%) related to cocaine- and amphetamine-regulated transcript (CART), a peptide involved in the regulation of food intake. Surprisingly, several retrotransposon-like sequences (1.0%) were found in the library. It may be that their presence accounts for some of the variation in venom toxins. The toxin category (18.8%) included natterins (18%), which are a new group of kininogenases recently described by our group, and a group of C-type lectins (0.8%). In addition, a considerable number of sequences (32%) was not related to sequences in the databases, which indicates that a great number of new toxins and proteins are still to be discovered from this fish venom gland.
Characterization of β-leptinotarsin-h and the effects of calcium flux antagonists on its activity
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β-Leptinotarsin-h, purified from the hemolymph of the beetle Leptinotarsa haldemani, is a potent (∼1 nM) neuroactive protein that rapidly (few seconds) stimulates Ca²⁺ influx and neurotransmitter release. Our goals were to further characterize β-leptinotarsin-h and to test the hypothesis that it stimulates Ca²⁺ influx through presynaptic Ca²⁺ channels. Analysis of partial amino acid sequences revealed that β-leptinotarsin-h is a unique protein with significant similarity to only one other protein, the juvenile hormone esterase of Leptinotarsa decemlineata, commonly known as the Colorado potato beetle. We have examined the effect of β-leptinotarsin-h on Ca²⁺ current, Ca²⁺ uptake, Ca²⁺ levels, and neurotransmitter release in synaptosomes, cell lines, and neuronal systems. We found that its preferred site of action appears to be mammalian presynaptic nerve terminals. We tested antagonists of Ca²⁺ flux for their effects on β-leptinotarsin-h-stimulated Ca²⁺ uptake in rat brain synaptosomes. The non-selective Ca²⁺ channel blockers flunarizine, Ni²⁺, ruthenium red, high-concentration thapsigargin, and SKF 96365 inhibited β-leptinotarsin-h's activity, but none of the tested selective blockers of voltage-operated Ca²⁺ channels (ω-agatoxin IVA, ω-conotoxin GVIA, ω-conotoxin MVIIC, nicardipine, nifedipine, SNX-482) was inhibitory. Selective inhibitors of ligand-operated, store-operated, and transduction-operated channels were also not inhibitory. β-Leptinotarsin-h did not stimulate Na⁺ uptake, ruling out Na⁺ channels and many non-selective cation channels as targets. We conclude that β-leptinotarsin-h stimulated Ca²⁺ uptake through presynaptic Ca²⁺ channels; which channel is yet to be determined. β-Leptinotarsin-h may prove to be a useful tool with which to investigate calcium channels and calcium flux.
Neurogranin expression in stably transfected N2A cell line affects cytosolic calcium level by nitric oxide stimulation
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To test a cellular effect of rodent neurogranin (Ng) oxidation as compared to Ng phosphorylation, we develop a cell model capable of stable expression of Ng using the Tet-On system, and determine whether Ng oxidation regulates intracellular calcium level. Our results show that Ng oxidation by nitric oxide donor induces an increase of [Ca²⁺]_i in Ng-expressed cells as compared to the control cells without expressing Ng. These results suggest that Ng oxidation plays a significant role in intracellular Ca²⁺ homeostasis, essential for the activated signaling networks in learning and memory.
S100A1 Is a Novel Molecular Chaperone and a Member of the Hsp70/Hsp90 Multichaperone Complex
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Although calmodulin is known to be a component of the Hsp70/Hsp90 multichaperone complex, the functional role of the protein remains uncertain. In this study, we have identified S100A1, but not calmodulin or other S100 proteins, as a potent molecular chaperone and a new member of the multichaperone complex. Glutathione S-transferase pull-down assays and co-immunoprecipitation experiments indicated the formation of stable complexes between S100A1 and Hsp90, Hsp70, FKBP52, and CyP40 both in vitro and in mammalian cells. S100A1 potently protected citrate synthase, aldolase, glyceraldehyde-3-phosphate dehydrogenase, and rhodanese from heat-induced aggregation and suppressed the aggregation of chemically denatured rhodanese and citrate synthase during the refolding pathway. In addition, S100A1 suppressed the heat-induced inactivation of citrate synthase activity, similar to that for Hsp90 and p23. The chaperone activity of S100A1 was antagonized by calmodulin antagonists, such as fluphenazine and prenylamine, that is, indeed an intrinsic function of the protein. The overexpression of S100A1 in COS-7 cells protected transiently expressed firefly luciferase and Escherichia coli β-galactosidase from inactivation during heat shock. The results demonstrate a novel physiological function for S100A1 and bring us closer to a comprehensive understanding of the molecular mechanisms of the Hsp70/Hsp90 multichaperone complex.
The transmembrane domain of syntaxin 1A negatively regulates voltage-sensitive Ca<sup>2+</sup> channels
2001, Neuroscience
Syntaxin 1A has a pronounced inhibitory effect on the activation kinetics and current amplitude of voltage-gated Ca²⁺ channels. This study explores the molecular basis of syntaxin interaction with N- and Lc-type Ca²⁺ channels by way of functional assays of channel gating in a Xenopus oocytes expression system. A chimera of syntaxin 1A and syntaxin 2 in which the transmembrane domain of syntaxin 2 replaced the transmembrane of syntaxin 1A (Sx1-2), significantly reduced the rate of activation of N- and Lc-channels. This shows a similar effect to that demonstrated by syntaxin 1A, though the current was not inhibited. The major sequence differences at the transmembrane of the syntaxin isoforms are that the two highly conserved cysteines Cys 271 and Cys 272 in syntaxin 1A correspond to the valines Val 272 and Val 273 in syntaxin 2 transmembrane. Mutating either cysteines in Sx1-1 (syntaxin 1A) to valines, did not affect modulation of the channel while a double mutant C271/272V was unable to regulate inward current. Transfer of these two cysteines to the transmembrane of syntaxin 2 by mutating Val 272 and Val 273 to Cys 272 and Cys 273 led to channel inhibition. When cleaved by botulinum toxin, the syntaxin 1A fragments, amino acids 1-253 and 254-288, which includes the transmembrane domain, were both unable to inhibit current amplitude but retained the ability to modify the activation kinetics of the channel. A full-length syntaxin 1A and the integrity of the two cysteines within the transmembrane are crucial for coordinating Ca²⁺ entry through the N- and Lc-channels.
These results suggest that upon membrane depolarization, the voltage-gated N- and Lc-type Ca²⁺-channels signal the exocytotic machinery by interacting with syntaxin 1A at the transmembrane and the cytosolic domains. Cleavage with botulinum toxin disrupts the coupling of the N- and Lc-type channels with syntaxin 1A and abolishes exocytosis, supporting the hypothesis that these channels actively participate in Ca²⁺ regulated secretion.

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Ca2+ and the regulation of neurotransmitter secretion

Abstract

J Biol Chem

Neuron

Neuron

J Neurosci

Proc Natl Acad Sci USA

Trends Neurosci

Cold Spring Harb Symp Quant Biol

Neuron

Proc Natl Acad Sci USA

Cell

Nature

J Biol Chem

Nature

J Biol Chem

J Biol Chem

J Biol Chem

J Biol Chem

Biochem J

J Biol Chem

Neuron

Proc Natl Acad Sci USA

Nature

Neuron

Nature

J Cell Biol

Annu Rev Physiol

Trends Neurosci

Science

Nature

The synaptic vesicle cycle: a cascade of protein-protein interactions

Nature

Synaptic vesicle biogenesis, docking, and fusion: a molecular description

Physiol Rev

Adaptation of Ca2+-triggered exocytosis in presynaptic terminals

Neuron

Definition of the readily releasable pool of vesicles at hippocampal synapses

Neuron

Kinetic analysis of secretion from permeabilized adrenal chromaffin cells reveals distinct components

J Biol Chem

Ca²⁺ and the regulation of neurotransmitter secretion

Adaptation of Ca²⁺-triggered exocytosis in presynaptic terminals