Cross-talk between metabotropic glutamate receptor 7 and beta adrenergic receptor signaling at cerebrocortical nerve terminals

Ferrero, José Javier; Ramírez‐Franco, Jorge; Martín, Ricardo; Bartolomé-Martı́n, David; Torres, Magdalena; Sánchez‐Prieto, José

doi:10.1016/j.neuropharm.2015.07.025

Cited by 17 publications

(19 citation statements)

References 66 publications

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“…However, a more recent account supports the role of EPAC in enhancing glutamate release in direct correlation to Munc13-1 translocation and binding with RIM1␣ in synaptosomes from the cerebral cortex. This EPAC-modulated translocation involves the activation of PLC to hydrolyze PIP 2 and generate DAG which activates and redistributes Munc13-1 to the active zone (301). Furthermore, EPAC activation increased RIM1␣ association with Rab3A to shift vesicles closer to the presynaptic membrane as shown by electron microscopy (300).…”

Section: Synaptic Neurotransmissionmentioning

confidence: 94%

“…Excessive excitatory stimuli associated with augmented glutamate release is often associated with seizure vulnerability, and intriguingly, EPAC is observed to enhance glutamate transmitter release in the presynaptic neurons by enhancing vesicle localization to the synaptic active zone through regulated localization of RIM1␣/Rab3 and Munc13-1 (see sect. IVA1A) (300,301). Furthermore, loss of EPAC1/2 in mice is observed to attenuate glutamate release in presynaptic terminals (1155).…”

Section: Autism and Neurodevelopmental Disordersmentioning

confidence: 96%

“…EPAC is observed to be a major regulator in presynaptic terminal release probability of synaptic vesicles (490,852,897). This is accomplished through a signalosome where EPAC2 binds Rim1␣, increasing association with Rab3 to maneuver synaptic vesicles in closer proximity to the plasma membrane (300,301). Furthermore, EPAC2-mediated generation of DAG through the PLC pathway may be involved in the activation and translocation of Munc13-1 promoting binding to Rim1␣ and subsequent SNARE-mediated synaptic vesicle release (301).…”

Section: Epac2 Signalosomes At Insulin-secreting Granules and Synaptimentioning

confidence: 99%

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Intracellular cAMP Sensor EPAC: Physiology, Pathophysiology, and Therapeutics Development

Robichaux

Cheng

2018

Physiological Reviews

158

226

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This review focuses on one family of the known cAMP receptors, the exchange proteins directly activated by cAMP (EPACs), also known as the cAMP-regulated guanine nucleotide exchange factors (cAMP-GEFs). Although EPAC proteins are fairly new additions to the growing list of cAMP effectors, and relatively "young" in the cAMP discovery timeline, the significance of an EPAC presence in different cell systems is extraordinary. The study of EPACs has considerably expanded the diversity and adaptive nature of cAMP signaling associated with numerous physiological and pathophysiological responses. This review comprehensively covers EPAC protein functions at the molecular, cellular, physiological, and pathophysiological levels; and in turn, the applications of employing EPAC-based biosensors as detection tools for dissecting cAMP signaling and the implications for targeting EPAC proteins for therapeutic development are also discussed.

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Section: Synaptic Neurotransmissionmentioning

confidence: 94%

Section: Autism and Neurodevelopmental Disordersmentioning

confidence: 96%

Section: Epac2 Signalosomes At Insulin-secreting Granules and Synaptimentioning

confidence: 99%

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Intracellular cAMP Sensor EPAC: Physiology, Pathophysiology, and Therapeutics Development

Robichaux

Cheng

2018

Physiological Reviews

158

226

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“…; Ferrero et al . ). Direct evidence that mGlu 7 receptors potentiate neurotransmitter release was obtained from synaptosomes (Martín et al .…”

Section: Discussionmentioning

confidence: 97%

“…; Ferrero et al . ). Thus, mGlu 7 receptor coupling to PLC‐dependent pathways in synaptosomes results in the net potentiation of release, despite the ongoing inhibition of Ca 2+ channels (Martín et al .…”

Section: Discussionmentioning

confidence: 97%

Bidirectional modulation of glutamatergic synaptic transmission by metabotropic glutamate type 7 receptors at Schaffer collateral–CA1 hippocampal synapses

Martín

Ferrero

Collado-Alsina

et al. 2018

The Journal of Physiology

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Neurotransmitter release is driven by Ca influx at synaptic boutons that acts on synaptic vesicles ready to undergo exocytosis. Neurotransmitter release is inhibited when metabotropic glutamate type 7 (mGlu ) receptors provoke a reduction in Ca influx, although the reduced release from synapses lacking this receptor suggests that they may also prime synaptic vesicles for release. These mGlu receptors activate phospholipase C (PLC) and generate inositol trisphosphate, which in turn releases Ca from intracellular stores and produces diacylglycerol (DAG), an activator of proteins containing DAG-binding domains such as Munc13 and protein kinase C (PKC). However, the full effects of mGlu receptor signalling on synaptic transmission are unclear. We found that prolonged activation of mGlu receptors with the agonist l-AP4 first reduces and then enhances the amplitude of EPSCs, a presynaptic effect that changes the frequency but not the amplitude of the mEPSCs and the paired pulse ratio. Pertussis toxin blocks the inhibitory response, while the PLC inhibitor U73122, and the inhibitor of DAG binding calphostin C, prevent receptor mediated potentiation. Moreover, this DAG-dependent potentiation of the release machinery brings more synaptic vesicles closer to the active zone plasma membrane in a Munc13-2- and RIM1α-dependent manner. Electrically evoked release of glutamate that activates mGlu receptors also bidirectionally modulates synaptic transmission. In these conditions, potentiation now occurs rapidly and it overcomes any inhibition, such that potentiation prevails unless it is suppressed with the PLC inhibitor U73122.

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Enriched environment ameliorates chronic temporal lobe epilepsy‐induced behavioral hyperexcitability and restores synaptic plasticity in CA3–CA1 synapses in male Wistar rats

Salaka

Nair

Annamalai

et al. 2021

J of Neuroscience Research

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Temporal lobe epilepsy (TLE) is the most common form of focal epilepsies.Pharmacoresistance and comorbidities pose significant challenges to its treatment necessitating the development of non-pharmacological approaches. In an earlier study, exposure to enriched environment (EE) reduced seizure frequency and duration and ameliorated chronic epilepsy-induced depression in rats. However, the cellular basis of beneficial effects of EE remains unknown. Accordingly, in the current study, we evaluated the effects of EE in chronic epilepsy-induced changes in behavioral hyperexcitability, synaptic transmission, synaptophysin (SYN), and calbindin (CB) expression, hippocampal subfield volumes and cell density in male Wistar rats.Epilepsy was induced by lithium-pilocarpine-induced status epilepticus. Chronic epilepsy resulted in behavioral hyperexcitability, decreased basal synaptic transmission, increased paired-pulse facilitation ratio, decreased hippocampal subfields volumes. Moreover, epileptic rats showed decreased synaptophysin and CB expression in the hippocampus. Six weeks post-SE, epileptic rats were exposed to EE for 2 weeks, 6 hr/ day. EE significantly reduced the behavioral hyperexcitability and restored basal synaptic transmission correlating with increased expression of SYN and CB. Our results reaffirm the beneficial effects of EE on behavior in chronic epilepsy and establishes some of the putative cellular mechanisms. Since drug resistance and comorbidities are a major concern in TLE, we propose EE as a potent non-pharmacological treatment modality to mitigate these changes in chronic epilepsy.

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Cross-talk between metabotropic glutamate receptor 7 and beta adrenergic receptor signaling at cerebrocortical nerve terminals

Cited by 17 publications

References 66 publications

Intracellular cAMP Sensor EPAC: Physiology, Pathophysiology, and Therapeutics Development

Intracellular cAMP Sensor EPAC: Physiology, Pathophysiology, and Therapeutics Development

Bidirectional modulation of glutamatergic synaptic transmission by metabotropic glutamate type 7 receptors at Schaffer collateral–CA1 hippocampal synapses

Enriched environment ameliorates chronic temporal lobe epilepsy‐induced behavioral hyperexcitability and restores synaptic plasticity in CA3–CA1 synapses in male Wistar rats

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