Calcium Release from Stores Inhibits GIRK

Kramer, P.; Williams, John T.

doi:10.1016/j.celrep.2016.11.076

Cited by 19 publications

(9 citation statements)

References 37 publications

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“…Application of BaCl 2 (100 μM), which blocks GIRK channels (Gantz et al, 2013) produced an apparent inward current (−46.0±10.6 pA, Figure 2A) with GppNHp-but not GTP-containing internal solution (p = 0.0003, n = 9-16, Figure 2C). These data demonstrate that amplifying G protein signaling with GppNHp produces standing currents carried by G protein-gated ion channels, consistent with previous studies (Kramer and Williams, 2016; Loucif et al, 2006). In the continued presence of BaCl 2 , tonic GluD1 R current was measured following application of NASPM (Figure 2D).…”

Section: Resultssupporting

confidence: 92%

Tonic GluD1 channel current is independent of G protein activity in the dorsal raphe nucleus

Copeland

Gantz

2022

Preprint

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Previously, using electrophysiological recordings from adult male and female mouse brain slices containing the dorsal raphe nucleus, we showed that GluD1R channels carry ionic current and are modulated via activation of Gαq-coupled a1-adrenergic receptors (a1-AR) in a GTP-dependent manner (Gantz et al., 2020). GluD1R channels also carry a tonic cation current, generally ~-20 pA at subthreshold membrane potentials (Gantz et al., 2020). The origin of tonic GluD1R channel current is unknown. Here, using the same preparation, we show there is no role of on-going G protein-coupled receptor activity in generating or sustaining tonic GluD1R channel current. Neither augmentation nor disruption of G protein activity had an effect on tonic GluD1R current. These results reveal that tonic GluD1R current arises from a mechanism separate from on-going activity of G protein-coupled receptors. Under current clamp, block of GluD1R channels hyperpolarized the membrane by ~10 mV at subthreshold potentials leading to reduced excitability. Thus, GluD1R channels carry a G protein-independent tonic current that contributes to subthreshold drive of action potential firing in the dorsal raphe nucleus.

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Section: Resultssupporting

confidence: 92%

Tonic GluD1 channel current is independent of G protein activity in the dorsal raphe nucleus

Copeland

Gantz

2022

Preprint

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“…α-Syn overexpression reduces D2R-mediated autoinhibition Multiple channels and transporters regulate neuronal activity and intracellular calcium dynamics. Dopamine activation of D2 autoinhibitory receptors on dopamine neurons decreases neuronal activity 16,53,54,56,58 and intracellular calcium dynamics 52,55,[59][60][61][62] . Therefore, we tested the hypothesis that the observed disturbance in neuronal excitability and calcium dynamics in α-syn-overexpressing neurons is due to dysregulation of canonical D2R autoinhibition in these neurons.…”

Section: Resultsmentioning

confidence: 99%

α-Synuclein-induced dysregulation of neuronal activity contributes to murine dopamine neuron vulnerability

Dagra

Miller

Lin

et al. 2021

npj Parkinsons Dis.

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Pathophysiological damages and loss of function of dopamine neurons precede their demise and contribute to the early phases of Parkinson’s disease. The presence of aberrant intracellular pathological inclusions of the protein α-synuclein within ventral midbrain dopaminergic neurons is one of the cardinal features of Parkinson’s disease. We employed molecular biology, electrophysiology, and live-cell imaging to investigate how excessive α-synuclein expression alters multiple characteristics of dopaminergic neuronal dynamics and dopamine transmission in cultured dopamine neurons conditionally expressing GCaMP6f. We found that overexpression of α-synuclein in mouse (male and female) dopaminergic neurons altered neuronal firing properties, calcium dynamics, dopamine release, protein expression, and morphology. Moreover, prolonged exposure to the D2 receptor agonist, quinpirole, rescues many of the alterations induced by α-synuclein overexpression. These studies demonstrate that α-synuclein dysregulation of neuronal activity contributes to the vulnerability of dopaminergic neurons and that modulation of D2 receptor activity can ameliorate the pathophysiology. These findings provide mechanistic insights into the insidious changes in dopaminergic neuronal activity and neuronal loss that characterize Parkinson’s disease progression with significant therapeutic implications.

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“…This suggests an interesting scenario where GABA-B and D2 receptors may be arranged spatially into overlapping microdomains in which both receptors have access to GIRK channels and the NALCN signaling complex. Likewise, it has been shown that GIRK channels are inhibited by intracellular calcium but enhanced by internal sodium ions (Kramer and Williams, 2016; Wang et al, 2016). This raises the question of whether NALCN and GIRK channels colocalize in a complex with G i/o protein-coupled receptors and whether Na + flowing through NALCN channels potentiates GIRK currents.…”

Section: Discussionmentioning

confidence: 99%

Gi/o protein-coupled receptors in dopamine neurons inhibit the sodium leak channel NALCN

Philippart

Khaliq

2018

eLife

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Dopamine (D2) receptors provide autoinhibitory feedback onto dopamine neurons through well-known interactions with voltage-gated calcium channels and G protein-coupled inwardly-rectifying potassium (GIRK) channels. Here, we reveal a third major effector involved in D2R modulation of dopaminergic neurons - the sodium leak channel, NALCN. We found that activation of D2 receptors robustly inhibits isolated sodium leak currents in wild-type mice but not in NALCN conditional knockout mice. Intracellular GDP-βS abolished the inhibition, indicating a G protein-dependent signaling mechanism. The application of dopamine reliably slowed pacemaking even when GIRK channels were pharmacologically blocked. Furthermore, while spontaneous activity was observed in nearly all dopaminergic neurons in wild-type mice, neurons from NALCN knockouts were mainly silent. Both observations demonstrate the critical importance of NALCN for pacemaking in dopaminergic neurons. Finally, we show that GABA-B receptor activation also produces inhibition of NALCN-mediated currents. Therefore, we identify NALCN as a core effector of inhibitory G protein-coupled receptors.

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Calcium Release from Stores Inhibits GIRK

Cited by 19 publications

References 37 publications

Tonic GluD1 channel current is independent of G protein activity in the dorsal raphe nucleus

Tonic GluD1 channel current is independent of G protein activity in the dorsal raphe nucleus

α-Synuclein-induced dysregulation of neuronal activity contributes to murine dopamine neuron vulnerability

Gi/o protein-coupled receptors in dopamine neurons inhibit the sodium leak channel NALCN

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