Rab3-interacting Molecule γ Isoforms Lacking the Rab3-binding Domain Induce Long Lasting Currents but Block Neurotransmitter Vesicle Anchoring in Voltage-dependent P/Q-type Ca2+ Channels

Uriu, Yoshitsugu; Kiyonaka, Shigeki; Miki, Takafumi; Yagi, Masakuni; Akiyama, Satoshi; Mori, Etsuro; Nakao, Akito; Beedle, Aaron M.; Campbell, Kevin P.; Wakamori, Minoru; Mori, Yasuo

doi:10.1074/jbc.m110.101311

Cited by 47 publications

(77 citation statements)

References 85 publications

(49 reference statements)

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“…RIMs localize Ca 2+ influx to active zones adjacent to the sites of synaptic vesicle exocytosis by tethering Ca 2+ channels via their PDZ domains and PxxP sequences (14,18), and they additionally modulate Ca 2+ -channel function, possibly via an indirect interaction with β4 subunits (15,16,23). To determine the redundancy among RIM isoforms in supporting Ca 2+ -triggered neurotransmitter release and in sustaining presynaptic Ca 2+ influx, we monitored the Ca 2+ dependence of neurotransmitter release.…”

Section: Resultsmentioning

confidence: 99%

“…In addition to their Ca 2+ -channel tethering function via their PDZ domains (14), RIMs have been shown to inhibit voltage-dependent inactivation of Ca 2+ -channel opening via their C 2 B domains (15,16,23). Thus, we set out to test whether this mechanism contributes to the neurotransmitter release phenotype produced by the RIM1/2 double KO.…”

Section: Rim2γ Modulates Ca 2+ -Channel Properties In Vitro But Does Notmentioning

confidence: 99%

“…The first activity is mediated by a tripartite complex of RIMs, RIM-BPs, and Ca 2+ channels in which the RIM PDZ domains directly bind to the C-termini of N-and P/Q-type Ca 2+ channels, the RIM PxxP-sequences bind to RIM-BPs, and RIM-BPs, in turn, directly bind to the C-termini of Ca 2+ channels (14,17,18). The second activity is mediated by the RIM C 2 B-domain, possibly by binding to β4 subunits of Ca 2+ channels (15,16). However, the relative contributions of different RIM isoforms and of their interactions with Ca 2+ channels are unknown.…”

mentioning

confidence: 99%

“…Recent studies revealed that RIMs regulate presynaptic Ca 2+ channels via two independent mechanisms, namely by recruiting Ca 2+ channels to active zones (14) and by modulating Ca 2+ -channel opening times (15,16). The first activity is mediated by a tripartite complex of RIMs, RIM-BPs, and Ca 2+ channels in which the RIM PDZ domains directly bind to the C-termini of N-and P/Q-type Ca 2+ channels, the RIM PxxP-sequences bind to RIM-BPs, and RIM-BPs, in turn, directly bind to the C-termini of Ca 2+ channels (14,17,18).…”

mentioning

confidence: 99%

“…Gene deletion experiments (Table S1) showed that RIMs are essential for multiple aspects of neurotransmitter release (4, 6-10) and for presynaptic short-and long-term plasticity (4, 6, 11-13). However, how different RIM isoforms contribute to neurotransmitter release is unclear.Recent studies revealed that RIMs regulate presynaptic Ca 2+ channels via two independent mechanisms, namely by recruiting Ca 2+ channels to active zones (14) and by modulating Ca 2+ -channel opening times (15,16). The first activity is mediated by a tripartite complex of RIMs, RIM-BPs, and Ca 2+ channels in which the RIM PDZ domains directly bind to the C-termini of N-and P/Q-type Ca 2+ channels, the RIM PxxP-sequences bind to RIM-BPs, and RIM-BPs, in turn, directly bind to the C-termini of Ca 2+ channels (14, 17, 18).…”

mentioning

confidence: 99%

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RIM genes differentially contribute to organizing presynaptic release sites

Kaeser

Deng

Fan

et al. 2012

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

114

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Tight coupling of Ca 2+ channels to the presynaptic active zone is critical for fast synchronous neurotransmitter release. RIMs are multidomain proteins that tether Ca 2+ channels to active zones, dock and prime synaptic vesicles for release, and mediate presynaptic plasticity. Here, we use conditional knockout mice targeting all RIM isoforms expressed by the Rims1 and Rims2 genes to examine the contributions and mechanism of action of different RIMs in neurotransmitter release. We show that acute single deletions of each Rims gene decreased release and impaired vesicle priming but did not alter the extracellular Ca 2+ -responsiveness of release (which for Rims gene mutants is a measure of presynaptic Ca 2+ influx). Moreover, single deletions did not affect the synchronization of release (which depends on the close proximity of Ca 2+ channels to release sites). In contrast, deletion of both Rims genes severely impaired the Ca 2+ responsiveness and synchronization of release. RIM proteins may act on Ca 2+ channels in two modes: They tether Ca 2+ channels to active zones, and they directly modulate Ca 2+ -channel inactivation. The first mechanism is essential for localizing presynaptic Ca 2+ influx to nerve terminals, but the role of the second mechanism remains unknown. Strikingly, we find that although the RIM2 C 2 B domain by itself significantly decreased Ca 2+ -channel inactivation in transfected HEK293 cells, it did not rescue any aspect of the RIM knockout phenotype in cultured neurons. Thus, RIMs primarily act in release as physical Ca 2+ -channel tethers and not as Ca 2+ -channel modulators. Different RIM proteins compensate for each other in recruiting Ca 2+ channels to active zones, but contribute independently and incrementally to vesicle priming.I n a presynaptic nerve terminal, Ca 2+ triggers synaptic vesicle exocytosis at specialized sites called active zones. Among the major active zone proteins (e.g., RIMs, α-liprins, ELKS's, RIMBPs, Piccolo/Bassoon, and Munc13's), RIMs stand out because they bind to all other components of active zones and are involved in all central aspects of neurotransmitter release (1, 2). In vertebrates, two RIM genes (Rims1 and Rims2) synthesize five principal RIM isoforms from independent promoters (RIM1α, RIM1β, RIM2α, RIM2β, and RIM2γ; Fig. 1A); these isoforms are further diversified by alternative splicing (3-5). Moreover, two additional RIM genes (Rims3 and Rims4) produce only γ-isoforms, which are not further considered here. Gene deletion experiments (Table S1) showed that RIMs are essential for multiple aspects of neurotransmitter release (4, 6-10) and for presynaptic short-and long-term plasticity (4, 6, 11-13). However, how different RIM isoforms contribute to neurotransmitter release is unclear.Recent studies revealed that RIMs regulate presynaptic Ca 2+ channels via two independent mechanisms, namely by recruiting Ca 2+ channels to active zones (14) and by modulating Ca 2+ -channel opening times (15,16). The first activity is mediated by a tripartite complex of ...

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Section: Resultsmentioning

confidence: 99%

Section: Rim2γ Modulates Ca 2+ -Channel Properties In Vitro But Does Notmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

See 3 more Smart Citations

RIM genes differentially contribute to organizing presynaptic release sites

Kaeser

Deng

Fan

et al. 2012

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

114

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ROLE of exercise in maintaining the integrity of the neuromuscular junction

2013

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Physical activity plays an important role in preventing chronic disease in adults and the elderly. Exercise has beneficial effects on the nervous system, including at the neuromuscular junction (NMJ). Exercise causes hypertrophy of NMJs and improves recovery from peripheral nerve injuries, whereas decreased physical activity causes degenerative changes in NMJs. Recent studies have begun to elucidate molecular mechanisms underlying the beneficial effects of exercise. These mechanisms involve Bassoon, neuregulin-1, peroxisome proliferator-activated receptor gamma coactivator 1α, Insulin-like growth factor-1, glial cell line-derived neurotrophic factor, neurotrophin 4, Homer, and nuclear factor of activated T cells c1. For example, NMJ denervation and active zone decreases have been observed in aged NMJs, but these age-dependent degenerative changes can be ameliorated by exercise. This review will discuss the effects of exercise on the maintenance and regeneration of NMJs and will highlight recent insights into the molecular mechanisms underlying these exercise effects.

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