Cysteine String Protein Regulates G Protein Modulation of N-Type Calcium Channels

Magga, Johanna; Jarvis, Scott E.; Arnot, Michelle I.; Zamponi, Gerald W.; Braun, Janice E. A.

doi:10.1016/s0896-6273(00)00096-9

Cited by 115 publications

(111 citation statements)

References 48 publications

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“…Instead, in the absence of CSP␣, the calyx synapse developed an age-dependent functional impairment, consistent with a role for CSP␣ as part of a molecular chaperone that makes it possible for synapses to keep running for extended time periods (2). Although this hypothesis was in agreement with previous observations in CSP-deficient flies (4), alternative hypotheses about the function of CSP were proposed based on the phenotype of CSP-deficient flies and on biochemical studies of protein-protein interactions mediated by CSP (7)(8)(9)(10)(11)(12)(13)(14).…”

supporting

confidence: 76%

CSPα-deficiency causes massive and rapid photoreceptor degeneration

Schmitz

Tabares²,

Khimich³

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

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Cysteine string protein (CSP) ␣ is an abundant synaptic vesicle protein that contains a DNA-J domain characteristic of Hsp40-type cochaperones. Previous studies showed that deletion of CSP␣ in mice leads to massive lethal neurodegeneration but did not clarify how the neurodegeneration affects specific subpopulations of neurons. Here, we analyzed the effects of the CSP␣ deficiency on tonically active ribbon synapses of the retina and the inner ear. We show that CSP␣-deficient photoreceptor terminals undergo dramatic and rapidly progressive neurodegeneration that starts before eye opening and initially does not affect other retinal synapses. These changes are associated with progressive blindness. In contrast, ribbon synapses of auditory hair cells did not exhibit presynaptic impairments in CSP␣-deficient mice. Hair cells, but not photoreceptor cells or central neurons, express CSP␤, thereby accounting for the lack of a hair-cell phenotype in CSP␣ knockout mice. Our data demonstrate that tonically active ribbon synapses in retina are particularly sensitive to the deletion of CSP␣ and that expression of at least one CSP isoform is essential to protect such tonically active synapses from neurodegeneration.hair cell ͉ ribbon synapse ͉ electroretinogram ͉ chaperone ͉ blindness S ynaptic vesicle exo-and endocytosis is mediated by a sophisticated machinery that allows nerve terminals to operate at high speed (1). Such continuous membrane traffic requires specific mechanisms to deal with the use-dependent aging and denaturation of proteins. One such mechanism may involve the synaptic vesicle protein cysteine string protein (CSP) ␣ that is thought to function as a cochaperone in presynaptic terminals (2, 3).CSP␣ is an abundant presynaptic protein (4) that contains a string of cysteine residues and a DNA-J domain that functionally collaborates with the DNA-K domains of Hsc70 proteins (reviewed in refs. 5 and 6). CSP␣ activates the ATPase activity of Hsc70 (7,8) and forms a trimeric complex with Hsc70 and the tetratricopeptide repeat protein SGT (3). This complex catalyzes the ATP-dependent refolding of denatured luciferase (3). Invertebrates have a single CSP gene, whereas mammals express three CSP genes: CSP␣ that is widely distributed but highly enriched in brain, and CSP␤ and CSP␥ that are primarily found in testis (2).Analyses of knockout (KO) mice revealed that CSP␣-deficient mice are relatively normal at birth but exhibit a progressive lethal phenotype that results in death after 2-4 months (2). Recordings in the Calyx of Held synapse of CSP␣ KO mice documented that CSP␣ is not required for N-, P͞Q-, and R-type Ca 2ϩ -channel function or Ca 2ϩ -triggered vesicle exocytosis. Instead, in the absence of CSP␣, the calyx synapse developed an age-dependent functional impairment, consistent with a role for CSP␣ as part of a molecular chaperone that makes it possible for synapses to keep running for extended time periods (2). Although this hypothesis was in agreement with previous observations in CSP-deficient flies (4), alt...

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supporting

confidence: 76%

CSPα-deficiency causes massive and rapid photoreceptor degeneration

Schmitz

Tabares²,

Khimich³

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

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“…106 Mammalian CSP was found to regulate presynaptic calcium channels 107 although it was not initially clear whether this action was the direct modulation of calcium influx or regulation of exocytotic machinery. 108 CSP interacts with the N-type 109 and P/Q-type 110,111 channel synprint motif (Fig. 2), and in case of N-type channels, appears to trigger a tonic G protein inhibition that involves on one hand a colocalization of the channel with Gβγ, and on the other, a GEF-like activity that leads to activation of Gα subunits.…”

Section: Functional Interactions Of Presynaptic Calcium Channels Withmentioning

confidence: 99%

Old proteins, developing roles: The regulation of calcium channels by synaptic proteins

Davies

Zamponi²

2008

Channels

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“…This same Csp-Hsc70-small glutamine-rich tetratricopeptide repeat-containing protein complex also interacts with heterotrimeric G-proteins. In this context Csp functions as a guanine-nucleotide exchange factor for G␣ S , which leads to stimulation of G-protein-dependent signaling and to G-protein-mediated inhibition of N-type Ca 2ϩ channels (20,21). Our laboratory previously established a novel role for Csp at endoplasmic reticulum (ER) membranes in modulating the trafficking of the cystic fibrosis transmembrane conductance regulator (CFTR).…”

mentioning

confidence: 99%

Cysteine String Protein Promotes Proteasomal Degradation of the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) by Increasing Its Interaction with the C Terminus of Hsp70-interacting Protein and Promoting CFTR Ubiquitylation

Schmidt

Watts

Aridor

et al. 2009

Journal of Biological Chemistry

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Cysteine string protein (Csp) is a J-domain-containing protein whose overexpression blocks the exit of cystic fibrosis transmembrane conductance regulator (CFTR) from the endoplasmic reticulum (ER). Another method of blocking ER exit, the overexpression of Sar1-GTP, however, yielded twice as much immature CFTR compared with Csp overexpression. This finding suggested that Csp not only inhibits CFTR ER exit but also facilitates the degradation of immature CFTR. This was confirmed by treatment with a proteasome inhibitor, which returned the level of immature CFTR to that found in cells expressing Sar1-GTP only. CspH43Q, which does not interact with Hsc70/Hsp70 efficiently, did not promote CFTR degradation, suggesting that the pro-degradative effect of Csp requires Hsc70/Hsp70 binding/activation. In agreement with this, Csp overexpression increased the amount of Hsc70/Hsp70 co-immunoprecipitated with CFTR, whereas overexpression of CspH43Q did not. The Hsc70/Hsp70 binding partner C terminus of Hsp70-interacting protein (CHIP) can target CFTR for proteasome-mediated degradation. Csp overexpression also increased the amount of CHIP co-immunoprecipitated with CFTR. In addition, CHIP interacted directly with Csp, which was confirmed by in vitro binding experiments. Csp overexpression also increased CFTR ubiquitylation and reduced the half-life of immature CFTR. These findings indicate that Csp not only regulates the exit of CFTR from the ER, but that this action is accompanied by Hsc70/ Hsp70 and CHIP-mediated CFTR degradation.Cysteine string protein (Csp, DnaJC5) 2 is a member of the DnaJ/Hsp40 protein chaperone family (1, 2). Csp contains a short N-terminal sequence, followed by the J-domain, a linker region, and the central cysteine-rich region, which gives these proteins their name. The cysteine residues in this region are post-translationally modified by the palmitate groups that serve for the membrane attachment of Csp (3). This structure is followed by a C-terminal domain, which is the most variable region among the three Csp paralogs in the human genome.Csp was originally discovered as an abundant protein in presynaptic junctions of Drosophila neurons (4). Csps are expressed at high levels in neurons and in cell types involved in regulated exocytosis (5-7), where they have been shown to govern exocytic secretory functions. For example, depolarizationinduced synaptic vesicle exocytosis is impaired in neurons from Csp-deficient Drosophila (8), and Csp overexpression produced decreases in stimulated insulin release from ␤-cells and stimulated catecholamine release from chromaffin cells (9 -11). Deletion of the Csp gene proved to be lethal both in Drosophila and in mice causing a progressive, fatal sensorimotor disorder characterized by developing neurodegenerative changes (12, 13).As for other Hsp40 homologs, the J-domain is responsible for the ability of Csp to bind Hsc70/Hsp70 and stimulate its ATPase activity (14). Similar to other chaperone proteins, Csp can be found in many different protein complexes in the...

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Cysteine String Protein Regulates G Protein Modulation of N-Type Calcium Channels

Cited by 115 publications

References 48 publications

CSPα-deficiency causes massive and rapid photoreceptor degeneration

CSPα-deficiency causes massive and rapid photoreceptor degeneration

Old proteins, developing roles: The regulation of calcium channels by synaptic proteins

Cysteine String Protein Promotes Proteasomal Degradation of the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) by Increasing Its Interaction with the C Terminus of Hsp70-interacting Protein and Promoting CFTR Ubiquitylation

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