Potentiation of Exocytosis by Phospholipase C-Coupled G-Protein-Coupled Receptors Requires the Priming Protein Munc13-1

Bauer, Claudia S.; Woolley, Robert J.; Teschemacher, Anja G.; Seward, Elizabeth P.

doi:10.1523/jneurosci.4201-06.2007

Cited by 66 publications

(59 citation statements)

References 65 publications

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“…IP 1 accumulation can be measured instead of inositol trisphosphate to monitor the activity of GPCRs linked to PLC in which LiCl inhibits inositol monophosphatase (27). A time course study showed that a 10 -20-min pre-exposure to L-AP4 is required to obtain maximal IP 1 accumulation (Fig.…”

Section: Resultsmentioning

confidence: 99%

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The Metabotropic Glutamate Receptor mGlu7 Activates Phospholipase C, Translocates Munc-13-1 Protein, and Potentiates Glutamate Release at Cerebrocortical Nerve Terminals

Martín

Durroux

Ciruela

et al. 2010

Journal of Biological Chemistry

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At synaptic boutons, metabotropic glutamate receptor 7 (mGlu7 receptor) serves as an autoreceptor, inhibiting glutamate release. In this response, mGlu7 receptor triggers pertussis toxin-sensitive G protein activation, reducing presynaptic Ca 2؉ influx and the subsequent depolarization evoked release. Here we report that receptor coupling to signaling pathways that potentiate release can be seen following prolonged exposure of nerve terminals to the agonist L-(؉)-phosphonobutyrate, L-AP4. This novel mGlu7 receptor response involves an increase in the release induced by the Ca 2؉ ionophore ionomycin, suggesting a mechanism that is independent of Ca 2؉ channel activity, but dependent on the downstream exocytotic release machinery. The mGlu7 receptor-mediated potentiation resists exposure to pertussis toxin, but is dependent on phospholipase C, and increased phosphatidylinositol (4,5)-bisphosphate hydrolysis. Furthermore, the potentiation of release does not depend on protein kinase C, although it is blocked by the diacylglycerolbinding site antagonist calphostin C. We also found that activation of mGlu7 receptors translocate the active zone protein essential for synaptic vesicle priming, munc13-1, from soluble to particulate fractions. We propose that the mGlu7 receptor can facilitate or inhibit glutamate release through multiple pathways, thereby exerting homeostatic control of presynaptic function.Metabotropic glutamate receptors belong to the G proteincoupled receptors (GPCRs) 2 superfamily and their eight receptor subtypes (mGlu1-8 receptors) are classified into three major groups. Most group III mGlu receptors (mGlu4, -6, -7, and -8 receptors) are located within the presynaptic active zone (1) where they act as autoreceptors mediating feedback inhibition of glutamate release (2-4). The signaling mechanism initiated by mGlu7 receptors to inhibit neurotransmitter release involves the activation of G i/o proteins that inhibit Ca 2ϩ channels and adenylyl cyclase (5), and probably the release process itself (6). However, mGlu7 receptor signaling is not restricted to these pathways. Thus, transfected mGlu7 receptors expressed in cerebellar granule cells inhibits somatic Ca 2ϩ currents by a mechanism that involves the activation of phospholipase C (PLC) and the hydrolysis of phosphatidylinositol (4,5)-bisphosphate thereby generating inositol trisphosphate that releases Ca 2ϩ from intracellular stores and diacylglycerol (DAG) that activates protein kinase C (PKC) (7). However, one important question that remains to be resolved is whether endogenous mGlu7 receptors at synaptic sites also signal via PLC and if so, what effect such signaling has on release modulation.Phorbol esters, stable analogues of the endogenous product of PLC, DAG, potentiate synaptic transmission by increasing neurotransmitter release (8 -15). DAG signaling at synapses has long been thought to be mediated by PKC and both presynaptic K ϩ and Ca 2ϩ channels, as well as other proteins of the release machinery, have been identified as PKC substrates....

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Section: Resultsmentioning

confidence: 99%

“…The active zone protein munc13-1 is a phorbol ester receptor essential for synaptic vesicle priming involved in neurotransmitter release potentiation (16,17,27). Munc13-1 is distributed in two biochemically distinguishable soluble and insoluble pools (16,28,29).…”

Section: Resultsmentioning

confidence: 99%

The Metabotropic Glutamate Receptor mGlu7 Activates Phospholipase C, Translocates Munc-13-1 Protein, and Potentiates Glutamate Release at Cerebrocortical Nerve Terminals

Martín

Durroux

Ciruela

et al. 2010

Journal of Biological Chemistry

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“…For example, in mammals M 1 , M 3 and M 5 subtypes of mAChRs are selectively linked to G q/11 proteins and activate phospholipase C whereas M 2 and M 4 subtypes are preferentially coupled to G j/0 proteins and inhibit adenylate cyclase (Caulfield & Birdsall, 1998;Langmead et al, 2008). Therefore ACh binding by M 2 subtypes receptors in many cases inhibits neurotransmitters release from neurons (Zhang, Chen, & Pan, 2007) while activation of M 1 receptors in contrast stimulates neurotransmitters release (Bauer, Woolley, Teschemacher, & Seward, 2007). In C. elegans GAR-2 mAChRs similarly with mammalian M 2 mAChRs mediate negative feedback in cholinergic motor neurons by inhibiting ACh release whereas ectopic expression of gar-3 in these neurons caused acceleration of ACh secretion (Dittman & Kaplan, 2008).…”

Section: Discussionmentioning

confidence: 99%

Acetylcholine Deficiency in Caenorhabditis elegans Induced by Hyperthermia Can Be Compensated by ACh-esterase Inhibition or Activation of GAR-3 mAChRs

Kalinnikova¹,

Шагидуллин²,

Колсанова³

et al. 2013

ENRR

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The nervous system is a target of hyperthermic failure of animal behavior. Caenorhabditis elegans can be used as an excellent model organism to investigate mechanisms underlying thermotolerance of nervous system. Inhibition of ACh-esterase by neostigmine produces rise in thermotolerance of C. elegans swimming induced by mechanical stimulus at constant temperature 36 °C. Protection of C. elegans behavior against heat stress by neostigmine indicates that hyperthermia induces ACh deficiency in the C. elegans nervous system which is one of the causes of hyperthermic failure of behavior. Activation of mAChRs by pilocarpine or oxotremorine M elevates behavior thermotolerance similarly with neostigmine while inhibition of these receptors by atropine has opposite effect. These results suggest that ACh protects C. elegans behavior against hyperthermia by binding with mAChRs. It is known that three G-protein coupled ACh receptors of C. elegans (GAR-1, GAR-2 and GAR-3) have sequence homology with five known subtypes of mammalian mAChRs. To identify mAChRs responsible for regulation of behavior response to hyperthermia we investigated effects of loss-of-function mutations in gar-1, gar-2 and gar-3 genes on the sensitivity of behavior thermotolerance to neostigmine and pilocarpine. Among them only loss-of-function gar-3 mutation caused insensitivity of C. elegans behavior thermotolerance to neostigmine and pilocarpine. Thus it is GAR-3 mAChR that mediates rise in behavior thermotolerance produced by ACh-esterase inhibitor neostigmine or agonists of mammalian mAChRs.

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“…The mAChR and AR pathways (M 1 and A 1 receptors) share a link mediated by the set phospholipase C-phosphatidylinositol 4,5-bisphosphate (PIP2)-diacylglycerol (DAG)-PKC, which modulates P/Q-type voltage-dependent calcium channels [34,43] . The phospholipase C-generated DAG also regulates the vesicle priming protein Munc13-1 and recruits ACh-containing vesicles for the immediately releasable pool [45] . M 2 -M 4 and A 2A receptors share the PKA pathway.…”

Section: Relation Between Machrs and Arsmentioning

confidence: 99%

Synergistic Action of Presynaptic Muscarinic Acetylcholine Receptors and Adenosine Receptors in Developmental Axonal Competition at the Neuromuscular Junction

Nadal

García²,

Hurtado³

et al. 2016

Dev Neurosci

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The development of the nervous system involves the initial overproduction of synapses, which promotes connectivity. Hebbian competition between axons with different activities leads to the loss of roughly half of the overproduced elements and this refines connectivity. We used quantitative immunohistochemistry to investigate, in the postnatal day 7 (P7) to P9 neuromuscular junctions, the involvement of muscarinic receptors (muscarinic acetylcholine autoreceptors and the M₁, M₂, and M₄ subtypes) and adenosine receptors (A₁ and A_2A subtypes) in the control of axonal elimination after the mouse levator auris longus muscle had been exposed to selective antagonists in vivo. In a previous study we analyzed the role of each of the individual receptors. Here we investigate the additive or occlusive effects of their inhibitors and thus the existence of synergistic activity between the receptors. The main results show that the A_2A, M₁, M₄, and A₁ receptors (in this order of ability) delayed axonal elimination at P7. M₄ produces some occlusion of the M₁ pathway and some addition to the A₁ pathway, which suggests that they cooperate. M₂ receptors may modulate (by allowing a permissive action) the other receptors, mainly M₄ and A₁. The continued action of these receptors (now including M₂ but not M₄) finally promotes axonal loss at P9. All 4 receptors (M₂, M₁, A₁, and A_2A, in this order of ability) are necessary. The M₄ receptor (which in itself does not affect axon loss) seems to modulate the other receptors. We found a synergistic action between the M₁, A₁, and A_2A receptors, which show an additive effect, whereas the potent M₂ effect is largely independent of the other receptors (though can be modulated by M₄). At P9, there is a full mutual dependence between the A₁ and A_2A receptors in regulating axon loss. In summary, postnatal axonal elimination is a regulated multireceptor mechanism that involves the cooperation of several muscarinic and adenosine receptor subtypes.

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Potentiation of Exocytosis by Phospholipase C-Coupled G-Protein-Coupled Receptors Requires the Priming Protein Munc13-1

Cited by 66 publications

References 65 publications

The Metabotropic Glutamate Receptor mGlu7 Activates Phospholipase C, Translocates Munc-13-1 Protein, and Potentiates Glutamate Release at Cerebrocortical Nerve Terminals

The Metabotropic Glutamate Receptor mGlu7 Activates Phospholipase C, Translocates Munc-13-1 Protein, and Potentiates Glutamate Release at Cerebrocortical Nerve Terminals

Acetylcholine Deficiency in Caenorhabditis elegans Induced by Hyperthermia Can Be Compensated by ACh-esterase Inhibition or Activation of GAR-3 mAChRs

Synergistic Action of Presynaptic Muscarinic Acetylcholine Receptors and Adenosine Receptors in Developmental Axonal Competition at the Neuromuscular Junction

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