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PMID:20452978

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Citation

Uriu, Y, Kiyonaka, S, Miki, T, Yagi, M, Akiyama, S, Mori, E, Nakao, A, Beedle, AM, Campbell, KP, Wakamori, M and Mori, Y (2010) Rab3-interacting molecule gamma isoforms lacking the Rab3-binding domain induce long lasting currents but block neurotransmitter vesicle anchoring in voltage-dependent P/Q-type Ca2+ channels. J. Biol. Chem. 285:21750-67

Abstract

Assembly of voltage-dependent Ca(2+) 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 beta-subunits physically interact with the long alpha isoform of the presynaptic active zone scaffolding protein RIM1 (RIM1alpha) via its C terminus containing the C(2)B domain. This interaction cooperates with RIM1alpha-Rab3 interaction to support neurotransmitter exocytosis by anchoring vesicles in the vicinity of VDCCs and by maintaining depolarization-triggered Ca(2+) 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 gamma isoforms (gamma-RIMs), carrying the C-terminal C(2)B domain common to RIMs but not the Rab3-binding region and other structural motifs present in the alpha-RIMs, including RIM1alpha. Here, we demonstrate that gamma-RIMs also exert prominent suppression of VDCC inactivation via direct binding to beta-subunits. In the pheochromocytoma PC12 cells, this common functional feature allows native RIMs to enhance acetylcholine secretion, whereas gamma-RIMs are uniquely different from alpha-RIMs in blocking localization of neurotransmitter-containing vesicles near the plasma membrane. Gamma-RIMs as well as alpha-RIMs show wide distribution in central neurons, but knockdown of gamma-RIMs attenuated glutamate release to a lesser extent than that of alpha-RIMs in cultured cerebellar neurons. The results suggest that sustained Ca(2+) 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 alpha-RIMs with gamma-RIMs for VDCC beta-subunits.

Links

PubMed PMC2898395 Online version:10.1074/jbc.M110.101311

Keywords

Animals; Brain/metabolism; Calcium Channels, N-Type/metabolism; Cricetinae; Electrophysiology/methods; Exocytosis; Humans; Mice; Mice, Inbred C57BL; Models, Biological; Neurons/metabolism; Neurotransmitter Agents/metabolism; PC12 Cells; Rats; Synaptic Transmission; Tissue Distribution; rab3 GTP-Binding Proteins/chemistry; rab3 GTP-Binding Proteins/metabolism

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

MOUSE:RIMS3

acts_upstream_of_or_within

GO:0042391: regulation of membrane potential

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:RIMS3

acts_upstream_of_or_within

GO:2000300: regulation of synaptic vesicle exocytosis

ECO:0000266: sequence orthology evidence used in manual assertion

UniProtKB:Q9JIR3

P

Seeded From UniProt

complete

MOUSE:RIMS3

enables

GO:0044325: ion channel binding

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

RAT:RIMS4

involved_in

GO:2000300: regulation of synaptic vesicle exocytosis

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:RIMS1

acts_upstream_of_or_within

GO:0042391: regulation of membrane potential

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:RIMS1

enables

GO:0044325: ion channel binding

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

MOUSE:RIMS2

acts_upstream_of_or_within

GO:0042391: regulation of membrane potential

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:RIMS2

enables

GO:0044325: ion channel binding

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

RAT:RIMS3

involved_in

GO:2000300: regulation of synaptic vesicle exocytosis

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:RIMS4

part_of

GO:0097060: synaptic membrane

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:RIMS4

enables

GO:0044325: ion channel binding

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

MOUSE:RIMS4

acts_upstream_of_or_within

GO:0042391: regulation of membrane potential

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete


See also

References

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