Transient Activation of GABAB Receptors Suppresses SK Channel Currents in Substantia Nigra Pars Compacta Dopaminergic Neurons

Estep, Chad M; Galtieri, Daniel; Zampese, Enrico; Goldberg, Joshua A.; Brichta, Lars; Greengard, Paul; Surmeier, D. James

doi:10.1371/journal.pone.0169044

Cited by 13 publications

(8 citation statements)

References 73 publications

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“…Next, we examined whether the blockade of the TRPC3 channel affects subthreshold membrane potentials of SNc DA neurons. In spontaneously firing DA neurons, application of tetrodotoxin (TTX), a voltage-dependent Na + channel blocker, completely suppressed spontaneous action potentials but slow oscillatory potentials (SOPs) survived in a slightly more depolarized state (Figures 2C and 2D), as previously reported (Nedergaard et al, 1993; Estep et al, 2016). These SOPs are not essential for pacemaking in DA neurons (Guzman et al, 2009), but are mediated by cyclic interactions between L-type Ca 2+ channels and Ca 2+ -dependent SK channels within an adequate range of membrane potentials (Ping and Shepard 1996; Wilson and Callaway, 2000).…”

Section: Resultssupporting

confidence: 83%

TRPC3 and NALCN channels drive pacemaking in substantia nigra dopaminergic neurons

Hahn

Kim

et al. 2021

Preprint

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Midbrain dopamine (DA) neurons are slow pacemakers that maintain extracellular DA levels. During the interspike intervals, subthreshold slow depolarization underlies autonomous pacemaking and determines its rate. However, the ion channels that determine slow depolarization are unknown. Here we show that TRPC3 and NALCN channels together form sustained inward currents responsible for the slow depolarization of nigral DA neurons. Specific TRPC3 channel blockade completely blocked DA neuron pacemaking, but the pacemaking activity in TRPC3 knock-out (KO) mice was perfectly normal, suggesting the presence of compensating ion channels. Blocking NALCN channels abolished pacemaking in both TRPC3 KO and wild-type mice. The NALCN current and mRNA and protein expression are increased in TRPC3 KO mice, indicating that NALCN compensates for TRPC3 currents. In normal conditions, TRPC3 and NALCN contribute equally to slow depolarization. Therefore, we conclude that TRPC3 and NALCN are two major leak channels that drive robust pacemaking in nigral DA neurons.

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Section: Resultssupporting

confidence: 83%

TRPC3 and NALCN channels drive pacemaking in substantia nigra dopaminergic neurons

Hahn

Kim

et al. 2021

Preprint

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“…PD is caused by progressive death of dopamine-secreting neurons within the substantia nigra of the midbrain [131, 132]. The substantia nigra sends dopaminergic projections to the basal ganglia that control balance and coordination, being responsible for the execution of voluntary movement [133]. In patients, the loss of dopaminergic inputs from the substantia nigra alters the balance of the output from the basal ganglia to the motor cortex causing the occurrence of motor (resting tremor, rigidity, and stooped posture) and nonmotor (gastrointestinal dysfunction, olfaction disability, and musculoskeletal pain) symptoms [132, 134–136].…”

Section: Training-evoked Increase In the Bdnf Level Reduces Motor mentioning

confidence: 99%

Health Benefits of Endurance Training: Implications of the Brain-Derived Neurotrophic Factor—A Systematic Review

Mrówczyński¹

2019

Neural Plasticity

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This article presents a concept that wide expression of brain-derived neurotrophic factor (BDNF) and its receptors (TrkB) in the nervous tissue, evoked by regular endurance training (ET), can cause numerous motor and metabolic adaptations, which are beneficial for human health. The relationships between the training-evoked increase of endogenous BDNF and molecular and/or physiological adaptations in the nervous structures controlling both motor performance and homeostasis of the whole organism have been presented. Due to a very wide range of plastic changes that ET has exerted on various systems of the body, the improvement of motor skills and counteraction of the development of civilization diseases resulting from the posttraining increase of BDNF/TrkB levels have been discussed, as important for people, who undertake ET. Thus, this report presents the influence of endurance exercises on the (1) transformation of motoneuron properties, which are a final element of the motor pathways, (2) reduction of motor deficits evoked by Parkinson disease, and (3) prevention of the metabolic syndrome (MetS). This review suggests that the increase of posttraining levels of BDNF and its TrkB receptors causes simultaneous changes in the activity of the spinal cord, the substantia nigra, and the hypothalamic nuclei neurons, which are responsible for the alteration of the functional properties of motoneurons innervating the skeletal muscles, for the enhancement of dopamine release in the brain, and for the modulation of hormone levels involved in regulating the metabolic processes, responsively. Finally, training-evoked increase of the BDNF/TrkB leads to a change in a manner of regulation of skeletal muscles, causes a reduction of motor deficits observed in the Parkinson disease, and lowers weight, glucose level, and blood pressure, which accompany the MetS. Therefore, BDNF seems to be the molecular factor of pleiotropic activity, important in the modulation processes, underlying adaptations, which result from ET.

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“…PKA activity increased the (Mpari et al, 2008) accumulation of SK channels into nanoclusters in somatodendritic spines of hippocampal neurons, and strongly restricted their expression to the soma, thus reducing SK channel function at the plasma membrane (Abiraman et al, 2016). Transient GABA B receptor stimulation in dopaminergic (DA) neurons in the substantia nigra caused irregular spiking which was evoked by reduced PKA activity and concomitant increasing surface SK channel expression in these neurons (Estep et al, 2016). In line with these observations, isoprenaline-mediated b-adrenergic stimulation of rat pyramidal neurons in the lateral amygdala activated PKA and induced SK channel internalization at the level of excitatory synapses (Faber et al, 2008).…”

Section: Regulation Of Sk Channel Activity and Localizationmentioning

confidence: 99%

Small conductance Ca 2+ -activated K + channels in the plasma membrane, mitochondria and the ER: Pharmacology and implications in neuronal diseases

Honrath

Krabbendam

Culmsee

et al. 2017

Neurochemistry International

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Ca-activated K (K) channels regulate after-hyperpolarization in many types of neurons in the central and peripheral nervous system. Small conductance Ca-activated K (K2/SK) channels, a subfamily of K channels, are widely expressed in the nervous system, and in the cardiovascular system. Voltage-independent SK channels are activated by alterations in intracellular Ca ([Ca]) which facilitates the opening of these channels through binding of Ca to calmodulin that is constitutively bound to the SK2 C-terminus. In neurons, SK channels regulate synaptic plasticity and [Ca] homeostasis, and a number of recent studies elaborated on the emerging neuroprotective potential of SK channel activation in conditions of excitotoxicity and cerebral ischemia, as well as endoplasmic reticulum (ER) stress and oxidative cell death. Recently, SK channels were discovered in the inner mitochondrial membrane and in the membrane of the endoplasmic reticulum which sheds new light on the underlying molecular mechanisms and pathways involved in SK channel-mediated protective effects. In this review, we will discuss the protective properties of pharmacological SK channel modulation with particular emphasis on intracellularly located SK channels as potential therapeutic targets in paradigms of neuronal dysfunction.

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Transient Activation of GABAB Receptors Suppresses SK Channel Currents in Substantia Nigra Pars Compacta Dopaminergic Neurons

Cited by 13 publications

References 73 publications

TRPC3 and NALCN channels drive pacemaking in substantia nigra dopaminergic neurons

TRPC3 and NALCN channels drive pacemaking in substantia nigra dopaminergic neurons

Health Benefits of Endurance Training: Implications of the Brain-Derived Neurotrophic Factor—A Systematic Review

Small conductance Ca 2+ -activated K + channels in the plasma membrane, mitochondria and the ER: Pharmacology and implications in neuronal diseases

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