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

Davies, Jonathan N.; Zamponi, Gerald W.

doi:10.4161/chan.2.2.6214

Cited by 18 publications

(12 citation statements)

References 151 publications

(191 reference statements)

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“…A large portion of CBD2 appears to be buried within the CRMP-2 tetrameric structure and may interfere with binding of the other CBDs by an as yet unclear mechanism. 3 This is consistent with the demonstration that large segments of the CRMP protein are involved in oligomerization (29).…”

Section: Identification Of Crmps As a Novel Casupporting

confidence: 86%

“…Enriched at functional release sites, CaV2.2 forms part of a large macromolecular complex, which facilitates efficient neurotransmitter release. Identification and analyses of protein-protein interactions within the nerve terminal have demonstrated a functional coupling between presynaptic Ca 2ϩ channels and the transmitter release machinery (1)(2)(3)(4). Because transmitter release is proportional to the third or fourth power of Ca 2ϩ entry (5-7), even small changes in intracellular Ca 2ϩ can elicit large changes in synaptic transmission.…”

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confidence: 99%

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An Atypical Role for Collapsin Response Mediator Protein 2 (CRMP-2) in Neurotransmitter Release via Interaction with Presynaptic Voltage-gated Calcium Channels

Brittain

Piekarz

Wang

et al. 2009

Journal of Biological Chemistry

182

285

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Collapsin response mediator proteins (CRMPs) specify axon/dendrite fate and axonal growth of neurons through protein-protein interactions. Their functions in presynaptic biology remain unknown. Here, we identify the presynaptic N-type Ca 2؉ channel (CaV2.2) as a CRMP-2-interacting protein. CRMP-2 binds directly to CaV2.2 in two regions: the channel domain I-II intracellular loop and the distal C terminus. Both proteins co-localize within presynaptic sites in hippocampal neurons. Overexpression in hippocampal neurons of a CRMP-2 protein fused to enhanced green fluorescent protein caused a significant increase in Ca 2؉ channel current density, whereas lentivirus-mediated CRMP-2 knockdown abolished this effect. Interestingly, the increase in Ca 2؉ current density was not due to a change in channel gating. Rather, cell surface biotinylation studies showed an increased number of CaV2.2 at the cell surface in CRMP-2-overexpressing neurons. These neurons also exhibited a significant increase in vesicular release in response to a depolarizing stimulus. Depolarization of CRMP-2-enhanced green fluorescent protein-overexpressing neurons elicited a significant increase in release of glutamate compared with control neurons. influx coincides with synapse formation, we sought to identify proteins that might modulate Ca 2ϩ channel behavior and transmitter release during synaptogenesis. A proteomic screen of growth cone-associated proteins (see supplemental Fig. S1) and proteins interacting with the ␣1B subunit of CaV2.2 (8) identified collapsin response mediator protein-2 (CRMP-2) as a candidate CaV2.2-interacting protein.CRMPs are intracellular phosphoproteins implicated in neuronal growth cone advance and migration (9 -13). In neurons, CRMPs are expressed in the lamellipodia and filopodia of growth cones, in the shafts of axons, and in cell bodies. They contribute to axon formation by binding to tubulin heterodimers and promoting assembly of microtubules (14). CRMP phosphorylation causes dissociation from microtubules, leading to axonal outgrowth arrest (10,15,16). Overexpression of CRMP-2 in cultured hippocampal neurons induces extra axons (12), whereas CRMP-3/4/5 have been shown to be necessary for neurite extension (10), branching (17), and growth cone formation (18). The breadth of interactions of CRMP proteins with motor proteins, kinases, enzymes, and endocytosis-exocytosis-related proteins suggests that CRMPs may serve as adaptors/scaffold molecules (10). Although neurotransmission was not affected in CRMP-1 knock-out mice (19), long term potentiation, spatial learning, and memory were affected in both CRMP-1 and CRMP-3 knock-out mice (19,20), suggesting a role for CRMPs in neurotransmission as well as synaptogenesis. As potential binding partners, CRMPs could affect neurotransmission by a physical interaction with either the synaptic machinery or CaV2.2 itself.

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Section: Identification Of Crmps As a Novel Casupporting

confidence: 86%

mentioning

confidence: 99%

An Atypical Role for Collapsin Response Mediator Protein 2 (CRMP-2) in Neurotransmitter Release via Interaction with Presynaptic Voltage-gated Calcium Channels

Brittain

Piekarz

Wang

et al. 2009

Journal of Biological Chemistry

182

285

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“…In some cases, these factors were found to influence G-protein regulation by modulation of channel inactivation properties [35,36]. Early reports also suggested that constituent proteins of the presynaptic vesicle release complex, known to be functionally coupled with neuronal voltage-gated Ca 2 + channels (for review see [8]), influence G-protein inhibition. For instance, changes in G-protein regulation of Ca v 2.2 channels were reported in the presence of syntaxin 1A [12,13,16].…”

Section: Introductionmentioning

confidence: 96%

Rim1 modulates direct G-protein regulation of Cav2.2 channels

Weiss

Sandoval

Kyonaka

et al. 2011

Pflugers Arch - Eur J Physiol

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Regulation of presynaptic voltage-gated calcium channels is critical for depolarization-evoked neurotransmitter release. Various studies attempted to determine the functional implication of Rim1, a component of the vesicle release machinery. Besides to couple voltage-gated Ca(2+) channels to the presynaptic vesicle release machinery, it was evidenced that Rim1 also prevents voltage-dependent inactivation of the channels through a direct interaction with the ancillary β-subunits, thus facilitating neurotransmitter release. However, facilitation of synaptic activity may also be caused by a reduction of the inhibitory pathway carried by G-protein-coupled receptors. Here, we explored the functional implication of Rim1 in G-protein regulation of Ca(v)2.2 channels. Activation of μ-opioid receptors expressed in HEK-293 cells along with Ca(v)2.2 channels produced a drastic current inhibition both in control and Rim1-expressing cells. In contrast, Rim1 considerably promoted the extent of current deinhibition following channel activation, favoring sustained Ca(2+) influx under prolonged activity. Our data suggest that Rim1-induced facilitation of neurotransmitter release may come as a consequence of a decrease in the inhibitory pathway carried by G-proteins that contributes, together with the slowing of channel inactivation, to maintain Ca(2+) influx under prolonged activity. The present study also furthers functional insights in the importance of proteins from the presynaptic vesicle complex in the regulation of voltage-gated Ca(2+) channels by G-proteins.

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“…157,158 Syntaxin, SNAP25 and synaptotagmin all bind to the synaptic protein interaction site (synprint site) on the II-III linker of Ca V 2 channels (Fig. 1).…”

Section: Acknowledgementsmentioning

confidence: 99%

G protein inhibition of Ca_V2 calcium channels

Currie¹

2010

Channels

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

Cited by 18 publications

References 151 publications

An Atypical Role for Collapsin Response Mediator Protein 2 (CRMP-2) in Neurotransmitter Release via Interaction with Presynaptic Voltage-gated Calcium Channels

An Atypical Role for Collapsin Response Mediator Protein 2 (CRMP-2) in Neurotransmitter Release via Interaction with Presynaptic Voltage-gated Calcium Channels

Rim1 modulates direct G-protein regulation of Cav2.2 channels

G protein inhibition of Ca_V2 calcium channels

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

Cited by 18 publications

References 151 publications

An Atypical Role for Collapsin Response Mediator Protein 2 (CRMP-2) in Neurotransmitter Release via Interaction with Presynaptic Voltage-gated Calcium Channels

An Atypical Role for Collapsin Response Mediator Protein 2 (CRMP-2) in Neurotransmitter Release via Interaction with Presynaptic Voltage-gated Calcium Channels

Rim1 modulates direct G-protein regulation of Cav2.2 channels

G protein inhibition of CaV2 calcium channels

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G protein inhibition of Ca_V2 calcium channels