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

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

Research output: Contribution to journalArticle

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Abstract

Assembly of voltage-dependent Ca2+ channels (VDCCs) with their associated proteins regulates the coupling of VDCCs with upstream and downstream cellular events. Among the four isoforms of the Rab3-interacting molecule (RIM1 to -4), we have previously reported that VDCC β-subunits physically interact with the long α isoform of the presynaptic active zone scaffolding protein RIM1 (RIM1α) via its C terminus containing the C 2B domain. This interaction cooperates with RIM1α-Rab3 interaction to support neurotransmitter exocytosis by anchoring vesicles in the vicinity of VDCCs and by maintaining depolarization-triggered Ca2+ influx as a result of marked inhibition of voltage-dependent inactivation of VDCCs. However, physiological functions have not yet been elucidated for RIM3 and RIM4, which exist only as short γ isoforms (γ-RIMs), carrying the C-terminal C2B domain common to RIMs but not the Rab3-binding region and other structural motifs present in the α-RIMs, including RIM1α. Here, we demonstrate that γ-RIMs also exert prominent suppression of VDCC inactivation via direct binding to β-subunits. In the pheochromocytoma PC12 cells, this common functional feature allows native RIMs to enhance acetylcholine secretion, whereas γ-RIMs are uniquely different from α-RIMs in blocking localization of neurotransmitter-containing vesicles near the plasma membrane. γ-RIMs as well as α-RIMs show wide distribution in central neurons, but knockdown of γ-RIMs attenuated glutamate release to a lesser extent than that of α-RIMs in cultured cerebellar neurons. The results suggest that sustained Ca2+ influx through suppression of VDCC inactivation by RIMs is a ubiquitous property of neurons, whereas the extent of vesicle anchoring to VDCCs at the plasma membrane may depend on the competition of α-RIMs with γ-RIMs for VDCC β-subunits.

Original languageEnglish
Pages (from-to)21750-21767
Number of pages18
JournalJournal of Biological Chemistry
Volume285
Issue number28
DOIs
Publication statusPublished - 09-07-2010

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Reaction injection molding
Neurotransmitter Agents
Protein Isoforms
Neurons
Molecules
Electric potential
Cell Membrane
PC12 Cells
Exocytosis
Pheochromocytoma
Acetylcholine
Glutamic Acid
Proteins
Cell membranes
Depolarization

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Uriu, Yoshitsugu ; Kiyonaka, Shigeki ; Miki, Takafumi ; Yagi, Masakuni ; Akiyama, Satoshi ; Mori, Emiko ; Nakao, Akito ; Beedle, Aaron M. ; Campbell, Kevin P. ; Wakamori, Minoru ; Mori, Yasuo. / 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. In: Journal of Biological Chemistry. 2010 ; Vol. 285, No. 28. pp. 21750-21767.
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abstract = "Assembly of voltage-dependent Ca2+ channels (VDCCs) with their associated proteins regulates the coupling of VDCCs with upstream and downstream cellular events. Among the four isoforms of the Rab3-interacting molecule (RIM1 to -4), we have previously reported that VDCC β-subunits physically interact with the long α isoform of the presynaptic active zone scaffolding protein RIM1 (RIM1α) via its C terminus containing the C 2B domain. This interaction cooperates with RIM1α-Rab3 interaction to support neurotransmitter exocytosis by anchoring vesicles in the vicinity of VDCCs and by maintaining depolarization-triggered Ca2+ influx as a result of marked inhibition of voltage-dependent inactivation of VDCCs. However, physiological functions have not yet been elucidated for RIM3 and RIM4, which exist only as short γ isoforms (γ-RIMs), carrying the C-terminal C2B domain common to RIMs but not the Rab3-binding region and other structural motifs present in the α-RIMs, including RIM1α. Here, we demonstrate that γ-RIMs also exert prominent suppression of VDCC inactivation via direct binding to β-subunits. In the pheochromocytoma PC12 cells, this common functional feature allows native RIMs to enhance acetylcholine secretion, whereas γ-RIMs are uniquely different from α-RIMs in blocking localization of neurotransmitter-containing vesicles near the plasma membrane. γ-RIMs as well as α-RIMs show wide distribution in central neurons, but knockdown of γ-RIMs attenuated glutamate release to a lesser extent than that of α-RIMs in cultured cerebellar neurons. The results suggest that sustained Ca2+ influx through suppression of VDCC inactivation by RIMs is a ubiquitous property of neurons, whereas the extent of vesicle anchoring to VDCCs at the plasma membrane may depend on the competition of α-RIMs with γ-RIMs for VDCC β-subunits.",
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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, Emiko; Nakao, Akito; Beedle, Aaron M.; Campbell, Kevin P.; Wakamori, Minoru; Mori, Yasuo.

In: Journal of Biological Chemistry, Vol. 285, No. 28, 09.07.2010, p. 21750-21767.

Research output: Contribution to journalArticle

TY - JOUR

T1 - 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

AU - Uriu, Yoshitsugu

AU - Kiyonaka, Shigeki

AU - Miki, Takafumi

AU - Yagi, Masakuni

AU - Akiyama, Satoshi

AU - Mori, Emiko

AU - Nakao, Akito

AU - Beedle, Aaron M.

AU - Campbell, Kevin P.

AU - Wakamori, Minoru

AU - Mori, Yasuo

PY - 2010/7/9

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N2 - Assembly of voltage-dependent Ca2+ channels (VDCCs) with their associated proteins regulates the coupling of VDCCs with upstream and downstream cellular events. Among the four isoforms of the Rab3-interacting molecule (RIM1 to -4), we have previously reported that VDCC β-subunits physically interact with the long α isoform of the presynaptic active zone scaffolding protein RIM1 (RIM1α) via its C terminus containing the C 2B domain. This interaction cooperates with RIM1α-Rab3 interaction to support neurotransmitter exocytosis by anchoring vesicles in the vicinity of VDCCs and by maintaining depolarization-triggered Ca2+ influx as a result of marked inhibition of voltage-dependent inactivation of VDCCs. However, physiological functions have not yet been elucidated for RIM3 and RIM4, which exist only as short γ isoforms (γ-RIMs), carrying the C-terminal C2B domain common to RIMs but not the Rab3-binding region and other structural motifs present in the α-RIMs, including RIM1α. Here, we demonstrate that γ-RIMs also exert prominent suppression of VDCC inactivation via direct binding to β-subunits. In the pheochromocytoma PC12 cells, this common functional feature allows native RIMs to enhance acetylcholine secretion, whereas γ-RIMs are uniquely different from α-RIMs in blocking localization of neurotransmitter-containing vesicles near the plasma membrane. γ-RIMs as well as α-RIMs show wide distribution in central neurons, but knockdown of γ-RIMs attenuated glutamate release to a lesser extent than that of α-RIMs in cultured cerebellar neurons. The results suggest that sustained Ca2+ influx through suppression of VDCC inactivation by RIMs is a ubiquitous property of neurons, whereas the extent of vesicle anchoring to VDCCs at the plasma membrane may depend on the competition of α-RIMs with γ-RIMs for VDCC β-subunits.

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