RIBEYE, a Component of Synaptic Ribbons

Schmitz, Frank; Königstorfer, Andreas; Südhof, Thomas C.

doi:10.1016/s0896-6273(00)00159-8

Cited by 496 publications

(295 citation statements)

References 46 publications

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“…In contrast to CtBP1, the N-terminal sequences of the CtBP2 isoforms might be critically important for their differential localization. The CtBP2 isoform RIBEYE is a large (985 amino acids) cytoplasmic protein that is exclusively expressed at synaptic ribbons of the central nervous system (9,31,44). RIBEYE contains a large N-terminal domain (560 amino acids) fused to a C-terminal (425 amino acid) region of CtBP2, resulting in a precise deletion of the N-terminal 20 amino acids of CtBP2 (see Fig.…”

Section: Discussionmentioning

confidence: 99%

“…Studies with mutant mice with targeted inactivation of the Ctbp genes suggest that they play important roles in multiple developmental processes during mouse development (7). In addition to CtBP1 and CtBP2, mammals also express an isoform of CtBP1 termed CtBP1-S/BARS (8) and an isoform of CtBP2 designated as RIBEYE (9) that are generated by differential RNA splicing and promoter utilization. The vertebrate CtBPs (6, 10 -13) and the Drosophila homolog, dCtBP (14,15), function as transcriptional corepressors.…”

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confidence: 99%

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Acetylation by p300 Regulates Nuclear Localization and Function of the Transcriptional Corepressor CtBP2

Zhao

Subramanian

Zhou

et al. 2006

Journal of Biological Chemistry

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CtBP family members, CtBP1 and CtBP2, are unique transcriptional regulators that adapt a metabolic enzyme fold, and their activities are regulated by NAD(H)-binding. CtBP1 is both cytoplasmic and nuclear, and its subcellular localization is regulated by sumoylation, phosphorylation, and binding to a PDZ protein. In contrast, we showed that CtBP2 is exclusively nuclear. CtBP1 and CtBP2 are highly similar, but differ at the N-terminal 20 amino acid region. Substitution of the N-terminal domain of CtBP1 with the corresponding CtBP2 domain confers a dominant nuclear localization pattern to CtBP1. The N-terminal domain of CtBP2 contains three Lys residues. Our results show that these Lys residues are acetylated by the nuclear acetylase p300. Although all three Lys residues of CtBP2 (Lys-6, Lys-8, and Lys-10) appear to be acetylated, acetylation of Lys-10 is critical for nuclear localization. CtBP2 with a single amino acid substitution at Lys-10 (K10R) is predominantly localized in the cytoplasm. The cytoplasmic localization of the K10R mutant is correlated with enhanced nuclear export that is inhibited by leptomycin B. Furthermore, lack of acetylation at Lys-10 renders CtBP2 to be more efficient in repression of the E-cadherin promoter. Our studies have revealed the important roles of acetylation in regulating subcellular localization and transcriptional activity of CtBP2.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Acetylation by p300 Regulates Nuclear Localization and Function of the Transcriptional Corepressor CtBP2

Zhao

Subramanian

Zhou

et al. 2006

Journal of Biological Chemistry

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“…In contrast, the RRP estimate from ⌬C m measurements in mouse inner hair cells is Ϸ53-64 SVs per synapse, whereas the morphologically docked SV pool contains only [16][17][18][19][20][21][22][23][24][25][26][27][28][29][30]. Some of this difference may be due to the fact that synaptic exocytosis had not been inhibited before fixation, which in frog saccular hair cells reduced the number of docked SVs per synapse from 43 to 32 (11).…”

Section: Discussionmentioning

confidence: 99%

Frequency selectivity of synaptic exocytosis in frog saccular hair cells

Rutherford

Roberts

2006

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

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The ability to respond selectively to particular frequency components of sensory inputs is fundamental to signal processing in the ear. The frog (Rana pipiens) sacculus, which is used for social communication and escape behaviors, is an exquisitely sensitive detector of sounds and ground-borne vibrations in the 5-to 200-Hz range, with most afferent axons having best frequencies between 40 and 60 Hz. We monitored the synaptic output of saccular sensory receptors (hair cells) by measuring the increase in membrane capacitance (⌬Cm) that occurs when synaptic vesicles fuse with the plasmalemma. Strong stepwise depolarization evoked an exocytic burst that lasted 10 ms and corresponded to the predicted capacitance of all docked vesicles at synapses, followed by a 20-ms delay before additional vesicle fusion. Experiments using weak stimuli, within the normal physiological range for these cells, revealed a sensitivity to the temporal pattern of membrane potential changes. Interrupting a weak depolarization with a properly timed hyperpolarization increased ⌬Cm. Small sinusoidal voltage oscillations (؎5 mV centered at ؊60 mV) evoked a ⌬Cm that corresponded to 95 vesicles per s at each synapse at 50 Hz but only 26 vesicles per s at 5 Hz and 27 vesicles per s at 200 Hz (perforated patch recordings). This frequency selectivity was absent for larger sinusoidal oscillations (؎10 mV centered at ؊55 mV) and was largest for hair cells with the smallest sinusoidal-stimulievoked Ca 2؉ currents. We conclude that frog saccular hair cells possess an intrinsic synaptic frequency selectivity that is saturated by strong stimuli.afferent ͉ synaptic vesicle pool ͉ ribbon synapse ͉ capacitance ͉ tuning T he auditory and vestibular systems in the ear and the related mechanosensory and electrosensory organs of the lateral line employ a remarkable variety of mechanical and neural mechanisms to distinguish frequency components of sensory signals from Ͻ10 Hz to nearly 100 kHz (1, 2). In each of these organs, a sensory stimulus passes through one or more stages of mechanical or electrical filtering (3), leading to graded changes in the sensory receptor cell's membrane potential, V m . Oscillatory sensory stimuli usually produce oscillations in V m , with the greatest amplitude occurring at a preferred frequency. Hair cells in the frog sacculus possess a broadly tuned electrical filter that causes V m to oscillate preferentially at frequencies between 35 and 75 Hz (4), as well as spontaneous oscillations of the mechanosensory apparatus at frequencies between 5 and 50 Hz (5).At the hair cells' output synapses, the information contained in V m is transmitted by a chemical neurotransmitter (glutamate) to postsynaptic terminals and encoded as a train of action potentials that travel to the brain. Each of these afferent synapses contains a presynaptic dense body [also known as the synaptic body (SB) or synaptic ribbon] (Fig. 1a) similar to ribbon synapses in the retina. As at other chemical synapses, V m controls calcium influx through voltage-gated cal...

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“…(i) Retina: Immunofluorescence labeling was performed as described in ref. 30 by using previously characterized antibodies (22,27,(31)(32)(33); note that the CSP␣ antibody used (2) crossreacts with all CSP isoforms. (ii) Hair cells: Organs of Corti were fixed with 4% paraformaldehyde in 120 mM Na-phosphate buffer (1 h).…”

Section: Methodsmentioning

confidence: 99%

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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RIBEYE, a Component of Synaptic Ribbons

Cited by 496 publications

References 46 publications

Acetylation by p300 Regulates Nuclear Localization and Function of the Transcriptional Corepressor CtBP2

Acetylation by p300 Regulates Nuclear Localization and Function of the Transcriptional Corepressor CtBP2

Frequency selectivity of synaptic exocytosis in frog saccular hair cells

CSPα-deficiency causes massive and rapid photoreceptor degeneration

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