Voltage-gated calcium channels contribute to spontaneous glutamate release directly via nanodomain coupling or indirectly via calmodulin

Lee, Byoung Ju; Yang, Che Ho; Lee, Seung Yeon; Lee, Sukho; Kim, Yujin; Ho, Won‐Kyung

doi:10.1016/j.pneurobio.2021.102182

Cited by 12 publications

(27 citation statements)

References 51 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Intracellular 10 mM EGTA did not affect the effects of P/Q-, N-, or R-type blockers (0.1 μM ωagatoxin-IVA, 0.1 μM ω-conotoxin GVIA, and 100 μM NiCl 2 , respectively) on mEPSCs (Supplementary Fig. 4), which is consistent with the notion that the contribution of P/Q-, N-, and Rtype Ca 2+ channels is mediated by local Ca 2+ increases (30). There was no additive effect of Bay K on mEPSC frequency and eEPSC amplitude when all P/Q-, N-, and R-type VGCCs were blocked by the mixture of 0. ]…”

Section: Ltccs Regulate Both Spontaneous and Evoked Glutamate Releasesupporting

confidence: 88%

“…As a candidate for the high-affinity Ca 2+ sensor responsible for spontaneous release, Doc2 was suggested (58,59), though the Ca 2+ -dependency of Doc2 is controversial (60). However, several studies have shown that Ca 2+ -dependent component of spontaneous release is not mediated by basal Ca 2+ but by the local Ca 2+ increase induced by VGCC openings (30,41,61) or Ca 2+ release from the internal stores (30,62) shown to mediate spontaneous release in cortical neurons (63). Furthermore, several studies have shown that the apparent Ca 2+ -cooperativity for spontaneous release is not as low as previously thought but similar to that for evoked release (30,63).…”

Section: Discussionmentioning

confidence: 99%

“…Excitatory neurons were distinguished from inhibitory neurons by fast decay kinetics of synaptic currents (ranged from 3.4 to 13.8 ms with mean value of 6.9 ± 0.2 ms, supplementary Fig. 1, N = 94) as previously described (30). Miniature excitatory postsynaptic currents (mEPSCs) were recorded at the holding potential (HP) of -70 mV, while evoked excitatory postsynaptic currents (eEPSCs) were recorded by applying 2 ms depolarizing step pulses to 0 mV from the HP every 20 s. The mEPSC frequency and eEPSC amplitude measured under the experimental conditions were normalized to the control level.…”

Section: Ltccs Regulate Both Spontaneous and Evoked Glutamate Releasementioning

confidence: 99%

“…We previously reported that Ca 2+ -dependent spontaneous release in cultured hippocampal neurons is mediated by local Ca 2+ increase via the stochastic opening of P/Q-, N-, and R-type VGCCs (30).…”

Section: Ltccs Regulate Both Spontaneous and Evoked Glutamate Releasementioning

confidence: 99%

See 3 more Smart Citations

L-type Ca²⁺channels mediate regulation of glutamate release by subthreshold potential changes

Lee

Ryu

et al. 2023

Preprint

Self Cite

View full text Add to dashboard Cite

Subthreshold depolarization enhances neurotransmitter release evoked by action potentials and plays a key role in modulating synaptic transmission by combining analog and digital signals. This process is known to be Ca2+-dependent. However, the underlying mechanism of how small changes in basal Ca2+caused by subthreshold depolarization can regulate transmitter release triggered by a large increase in local Ca2+is not well understood. This study aimed to investigate the source and signaling mechanisms of Ca2+that couple subthreshold depolarization with the enhancement of glutamate release in hippocampal cultures and CA3 pyramidal neurons. Subthreshold depolarization increased presynaptic Ca2+levels, the frequency of spontaneous release, and the amplitude of evoked release, all of which were abolished by blocking L-type Ca2+channels. A high concentration of intracellular Ca2+buffer or blockade of calmodulin and phospholipase C abolished depolarization induced increases in transmitter release. Estimation of the readily releasable pool size using hypertonic sucrose showed depolarization induced increases in readily releasable pool size, and this increase was abolished by blockade of calmodulin or phospholipase C. Our results provide mechanistic insights into the modulation of transmitter release by subthreshold potential change and highlight the role of L-type Ca2+channels in coupling subthreshold depolarization to the activation of Ca2+-dependent signaling molecules that regulate transmitter release.SIGNIFICANCENeuronal activities are encoded by action potentials, but subthreshold changes in resting membrane potentials also play important roles in regulating neuronal functions including synaptic transmission. It is, however, poorly understood how small changes in basal Ca2+induced by subthreshold depolarization regulate transmitter release triggered by a large increase in local Ca2+in presynaptic terminals. We demonstrate that L-type Ca2+channels are the major source of presynaptic Ca2+influx at basal state and during subthreshold depolarization, resulting in the activation of signaling molecules such as calmodulin and phospholipase C, which facilitate transmitter release by increasing both release probability and the readily releasable pool size. Our results provide mechanistic insight into how subthreshold potential changes contribute to regulating transmitter release.

show abstract

Section: Ltccs Regulate Both Spontaneous and Evoked Glutamate Releasesupporting

confidence: 88%

Section: Discussionmentioning

confidence: 99%

Section: Ltccs Regulate Both Spontaneous and Evoked Glutamate Releasementioning

confidence: 99%

Section: Ltccs Regulate Both Spontaneous and Evoked Glutamate Releasementioning

confidence: 99%

See 2 more Smart Citations

L-type Ca²⁺channels mediate regulation of glutamate release by subthreshold potential changes

Lee

Ryu

et al. 2023

Preprint

Self Cite

View full text Add to dashboard Cite

show abstract

“…6 E ) or added a commonly used nonselective VGCC blocker, cadmium chloride (CdCl 2 ; Fig. 6 F ; Dascal et al, 1986 ; Tredway et al, 1999 ; Chin et al, 2003 ; Martínez Damonte et al, 2018 ; Lee et al, 2022 ) to block extracellular Ca 2+ entry via VGCCs. We found that in assays with Ca 2+ supplemented buffer, G-1 increased the intracellular Ca 2+ level in hippocampal neurons compared with vehicle ( Fig.…”

Section: Resultsmentioning

confidence: 99%

Differential Effects of the G-Protein-Coupled Estrogen Receptor (GPER) on Rat Embryonic (E18) Hippocampal and Cortical Neurons

Pemberton

Rosato

Dedert

et al. 2022

eNeuro

View full text Add to dashboard Cite

Estrogen plays fundamental roles in nervous system development and function. Traditional studies examining the effect of estrogen in the brain have focused on the nuclear estrogen receptors (ERs), ERα and ERβ. Studies related to the extranuclear, membrane-bound G proteincoupled estrogen receptor (GPER/GPR30) have revealed a neuroprotective role for GPER in mature neurons. In this study, we investigated the differential effects of GPER activation in primary rat embryonic (E18) hippocampal and cortical neurons. Microscopy imaging, multielectrode array (MEA), and Ca 2+ imaging experiments revealed that GPER activation with selective agonist, G-1, and non-selective agonist, 17β-estradiol (E2), increased neural growth, neural firing activity, and intracellular Ca 2+ more profoundly in hippocampal neurons than in cortical neurons. The GPER-mediated Ca 2+ rise in hippocampal neurons involve internal Ca 2+ store release via activation of phospholipase C and extracellular entry via Ca 2+ channels. 3Immunocytochemistry results revealed no observable difference in GPER expression/localization in neurons, yet RT-qPCR and western blot showed a higher GPER expression in the cortex than hippocampus, implying that GPER expression level may not fully account for its robust physiological effects in hippocampal neurons. We used RNA sequencing data to identify distinctly enriched pathways and significantly expressed genes in response to G-1 or E2 in cultured rat E18 hippocampal and cortical neurons. In summary, the identification of differential effects of GPER activation on hippocampal and cortical neurons in the brain and the determination of key genes and molecular pathways are instrumental toward an understanding of estrogen's action in early neuronal development. Significance StatementStudies of estrogen function via a non-nuclear G protein-coupled estrogen receptor (GPER/GPR30) in the brain have primarily focused on mature neurons and neuroprotective actions with little investigation into the role of GPER in early neural development. In this work, we discover differential effects of GPER on early neurite outgrowth, neuronal activity, and intracellular calcium signaling in primarily cultured rat embryonic (E18) hippocampal and cortical neurons. This study further highlights distinct, transcriptomic genes and pathways that are regulated by GPER agonists in early developing hippocampal and cortical neurons. These results advance our fundamental understanding of estrogen functions via GPER signaling in different (hippocampal versus cortical) neurons during early neuronal development. This knowledge is also instrumental for therapeutics for GPER-related neurodevelopmental disorders.

show abstract

Identification of Dp140 and α1-syntrophin as novel molecular interactors of the neuronal CaV2.1 channel

Leyva-Leyva

Sandoval

Morales‐Lázaro

et al. 2023

Pflugers Arch - Eur J Physiol

View full text Add to dashboard Cite

Voltage-gated calcium channels contribute to spontaneous glutamate release directly via nanodomain coupling or indirectly via calmodulin

Cited by 12 publications

References 51 publications

L-type Ca²⁺channels mediate regulation of glutamate release by subthreshold potential changes

L-type Ca²⁺channels mediate regulation of glutamate release by subthreshold potential changes

Differential Effects of the G-Protein-Coupled Estrogen Receptor (GPER) on Rat Embryonic (E18) Hippocampal and Cortical Neurons

Identification of Dp140 and α1-syntrophin as novel molecular interactors of the neuronal CaV2.1 channel

Contact Info

Product

Resources

About

Voltage-gated calcium channels contribute to spontaneous glutamate release directly via nanodomain coupling or indirectly via calmodulin

Cited by 12 publications

References 51 publications

L-type Ca2+channels mediate regulation of glutamate release by subthreshold potential changes

L-type Ca2+channels mediate regulation of glutamate release by subthreshold potential changes

Differential Effects of the G-Protein-Coupled Estrogen Receptor (GPER) on Rat Embryonic (E18) Hippocampal and Cortical Neurons

Identification of Dp140 and α1-syntrophin as novel molecular interactors of the neuronal CaV2.1 channel

Contact Info

Product

Resources

About

L-type Ca²⁺channels mediate regulation of glutamate release by subthreshold potential changes

L-type Ca²⁺channels mediate regulation of glutamate release by subthreshold potential changes