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Ca²⁺, Na⁺, and K⁺ Homeostasis and Signaling in Brain Development and Neurological Diseases

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A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cells of the Nervous System".

Deadline for manuscript submissions: closed (15 August 2022) | Viewed by 25432

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Dr. Anna Pannaccione

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Division of Pharmacology, Department of Neuroscience, Reproductive and Dentistry Sciences, School of Medicine, Federico II University of Naples, Naples, Italy

Special Issue Information

Dear Colleagues,

This Special Issue of Cells aims to gather collaborative efforts by several authors and reviewers to provide a collection of literature on the role played by calcium (Ca²⁺), sodium (Na⁺), and potassium (K⁺) in brain development and the etiopathogenesis of neurological diseases. This topic is currently extremely important since the regulation of ionic homeostasis is crucial for many neuronal functions. Ion gradients provide the driving force for important intra- and inter-cellular communications within neuronal networks. Na⁺ entry into neurons is crucial for triggering and the propagation of action potentials, whereas Ca²⁺ signaling is involved in neurotransmitter release, synaptic plasticity processes, gene expression, and other fundamental neuronal functions. The efflux of K⁺ ions through specific channels mediates the repolarization of membrane potential following depolarization. Growing evidence indicates that perturbation of ionic homeostasis is the primary signal that something is dysfunctional or diverging from normal physiology conditions. Under pathological conditions, a dyshomeostasis of Ca²⁺ is mostly caused by increasing intracellular Ca²⁺ concentrations. It has been hypothesized that elevations in intracellular Ca²⁺ coupled with alterations in endoplasmic reticulum/mitochondria interaction could cause metabolic derangement due to mitochondrial Ca²⁺ overload causing: (1) mitochondrial dysfunction, (2) excessive ROS generation, (3) loss of ATP production, and (4) Ca²⁺modulation dyshomeostasis involving both plasma membrane pumps and intracellular Ca²⁺ store machinery. The activity of many K⁺ and Na⁺ channels has been found to be deregulated in several neurological diseases. In addition, the activity of ion-motive ATPases is impaired in pathological brains, thus contributing to the alteration of Na⁺ and Ca²⁺ homeostasis by inducing membrane depolarization and the opening of voltage-sensitive channels. These disturbances contribute to neuronal dysfunctions, including the alteration of intrinsic neuronal excitability, and might trigger several cell death pathways contributing to neurological diseases.

Dr. Anna Pannaccione
Guest Editor

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Keywords

ionic homeostasis
glial cells
neurodegeneration
Ca²⁺ signaling
metabolic dysfunction
neuroprotection
neuronal differentiation

Published Papers (8 papers)

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Research

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23 pages, 3561 KiB

Open AccessArticle

TGF-β2 Regulates Transcription of the K⁺/Cl⁻ Cotransporter 2 (KCC2) in Immature Neurons and Its Phosphorylation at T1007 in Differentiated Neurons

by Anastasia Rigkou, Attila Magyar, Jan Manuel Speer and Eleni Roussa

Cells 2022, 11(23), 3861; https://doi.org/10.3390/cells11233861 - 30 Nov 2022

Cited by 2 | Viewed by 1071

Abstract

KCC2 mediates extrusion of K⁺ and Cl⁻ and assuresthe developmental “switch” in GABA function during neuronal maturation. However, the molecular mechanisms underlying KCC2 regulation are not fully elucidated. We investigated the impact of transforming growth factor beta 2 (TGF-β2) on KCC2 during neuronal maturation using quantitative RT-PCR, immunoblotting, immunofluorescence and chromatin immunoprecipitation in primary mouse hippocampal neurons and brain tissue from Tgf-β2-deficient mice. Inhibition of TGF-β/activin signaling downregulates Kcc2 transcript in immature neurons. In the forebrain of Tgf-β2^−/− mice, expression of Kcc2, transcription factor Ap2β and KCC2 protein is downregulated. AP2β binds to Kcc2 promoter, a binding absent in Tgf-β2^−/−. In hindbrain/brainstem tissue of Tgf-β2^−/− mice, KCC2 phosphorylation at T1007 is increased and approximately half of pre-Bötzinger-complex neurons lack membrane KCC2 phenotypes rescued through exogenous TGF-β2. These results demonstrate that TGF-β2 regulates KCC2 transcription in immature neurons, possibly acting upstream of AP2β, and contributes to the developmental dephosphorylation of KCC2 at T1007. The present work suggests multiple and divergent roles for TGF-β2 on KCC2 during neuronal maturation and provides novel mechanistic insights for TGF-β2-mediated regulation of KCC2 gene expression, posttranslational modification and surface expression. We propose TGF-β2 as a major regulator of KCC2 with putative implications for pathophysiological conditions. Full article

(This article belongs to the Special Issue Ca²⁺, Na⁺, and K⁺ Homeostasis and Signaling in Brain Development and Neurological Diseases)

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19 pages, 5598 KiB

Open AccessArticle

Increased K_V2.1 Channel Clustering Underlies the Reduction of Delayed Rectifier K⁺ Currents in Hippocampal Neurons of the Tg2576 Alzheimer’s Disease Mouse

by Ilaria Piccialli, Maria José Sisalli, Valeria de Rosa, Francesca Boscia, Valentina Tedeschi, Agnese Secondo and Anna Pannaccione

Cells 2022, 11(18), 2820; https://doi.org/10.3390/cells11182820 - 09 Sep 2022

Cited by 2 | Viewed by 1760

Abstract

Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by the progressive deterioration of cognitive functions. Cortical and hippocampal hyperexcitability intervenes in the pathological derangement of brain activity leading to cognitive decline. As key regulators of neuronal excitability, the voltage-gated K⁺ channels (K_V) might play a crucial role in the AD pathophysiology. Among them, the K_V2.1 channel, the main α subunit mediating the delayed rectifier K⁺ currents (I_DR) and controlling the intrinsic excitability of pyramidal neurons, has been poorly examined in AD. In the present study, we investigated the K_V2.1 protein expression and activity in hippocampal neurons from the Tg2576 mouse, a widely used transgenic model of AD. To this aim we performed whole-cell patch-clamp recordings, Western blotting, and immunofluorescence analyses. Our Western blotting results reveal that K_V2.1 was overexpressed in the hippocampus of 3-month-old Tg2576 mice and in primary hippocampal neurons from Tg2576 mouse embryos compared with the WT counterparts. Electrophysiological experiments unveiled that the whole I_DR were reduced in the Tg2576 primary neurons compared with the WT neurons, and that this reduction was due to the loss of the K_V2.1 current component. Moreover, we found that the reduction of the K_V2.1-mediated currents was due to increased channel clustering, and that glutamate, a stimulus inducing K_V2.1 declustering, was able to restore the I_DR to levels comparable to those of the WT neurons. These findings add new information about the dysregulation of ionic homeostasis in the Tg2576 AD mouse model and identify K_V2.1 as a possible player in the AD-related alterations of neuronal excitability. Full article

(This article belongs to the Special Issue Ca²⁺, Na⁺, and K⁺ Homeostasis and Signaling in Brain Development and Neurological Diseases)

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24 pages, 5945 KiB

Open AccessArticle

CaMKII Inhibition Attenuates Distinct Gain-of-Function Effects Produced by Mutant Nav1.6 Channels and Reduces Neuronal Excitability

by Agnes S. Zybura, Firoj K. Sahoo, Andy Hudmon and Theodore R. Cummins

Cells 2022, 11(13), 2108; https://doi.org/10.3390/cells11132108 - 04 Jul 2022

Cited by 2 | Viewed by 2285

Abstract

Aberrant Nav1.6 activity can induce hyperexcitability associated with epilepsy. Gain-of-function mutations in the SCN8A gene encoding Nav1.6 are linked to epilepsy development; however, the molecular mechanisms mediating these changes are remarkably heterogeneous and may involve post-translational regulation of Nav1.6. Because calcium/calmodulin-dependent protein kinase II (CaMKII) is a powerful modulator of Nav1.6 channels, we investigated whether CaMKII modulates disease-linked Nav1.6 mutants. Whole-cell voltage clamp recordings in ND7/23 cells show that CaMKII inhibition of the epilepsy-related mutation R850Q largely recapitulates the effects previously observed for WT Nav1.6. We also characterized a rare missense variant, R639C, located within a regulatory hotspot for CaMKII modulation of Nav1.6. Prediction software algorithms and electrophysiological recordings revealed gain-of-function effects for R639C mutant channel activity, including increased sodium currents and hyperpolarized activation compared to WT Nav1.6. Importantly, the R639C mutation ablates CaMKII phosphorylation at a key regulatory site, T642, and, in contrast to WT and R850Q channels, displays a distinct response to CaMKII inhibition. Computational simulations demonstrate that modeled neurons harboring the R639C or R850Q mutations are hyperexcitable, and simulating the effects of CaMKII inhibition on Nav1.6 activity in modeled neurons differentially reduced hyperexcitability. Acute CaMKII inhibition may represent a promising mechanism to attenuate gain-of-function effects produced by Nav1.6 mutations. Full article

(This article belongs to the Special Issue Ca²⁺, Na⁺, and K⁺ Homeostasis and Signaling in Brain Development and Neurological Diseases)

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29 pages, 7053 KiB

Open AccessArticle

GABA Receptors Can Depolarize the Neuronal Membrane Potential via Quantum Tunneling of Chloride Ions: A Quantum Mathematical Study

by Sager Nawafleh, Abdallah Barjas Qaswal, Aiman Suleiman, Obada Alali, Fuad Mohammed Zayed, Mohammad Abu Orabi Al-Adwan and Mo’ath Bani Ali

Cells 2022, 11(7), 1145; https://doi.org/10.3390/cells11071145 - 28 Mar 2022

Cited by 4 | Viewed by 4958

Abstract

GABA (gamma-aminobutyric acid) receptors represent the major inhibitory receptors in the nervous system and their inhibitory effects are mediated by the influx of chloride ions that tends to hyperpolarize the resting membrane potential. However, GABA receptors can depolarize the resting membrane potential and thus can also show excitatory effects in neurons. The major mechanism behind this depolarization is mainly attributed to the accumulation of chloride ions in the intracellular compartment. This accumulation leads to increase in the intracellular chloride concentration and depolarize the Nernst potential of chloride ions. When the membrane potential is relatively hyperpolarized, this will result in a chloride efflux instead of influx trying to reach their depolarized equilibrium potential. Here, we propose different mechanism based on a major consequence of quantum mechanics, which is quantum tunneling. The quantum tunneling model of ions is applied on GABA receptors and their corresponding chloride ions to show how chloride ions can depolarize the resting membrane potential. The quantum model states that intracellular chloride ions have higher quantum tunneling probability than extracellular chloride ions. This is attributed to the discrepancy in the kinetic energy between them. At physiological parameters, the quantum tunneling is negligible to the degree that chloride ions cannot depolarize the membrane potential. Under certain conditions such as early neuronal development, gain-of-function mutations, stroke and trauma that can lower the energy barrier of the closed gate of GABA receptors, the quantum tunneling is enhanced so that the chloride ions can depolarize the resting membrane potential. The major unique feature of the quantum tunneling mechanism is that the net efflux of chloride ions is attained without the need for intracellular accumulation of chloride ions as long as the energy barrier of the gate is reduced but still higher than the kinetic energy of the chloride ion as a condition for quantum tunneling to take place. Full article

(This article belongs to the Special Issue Ca²⁺, Na⁺, and K⁺ Homeostasis and Signaling in Brain Development and Neurological Diseases)

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21 pages, 4933 KiB

Open AccessArticle

KCNQ2 Selectivity Filter Mutations Cause Kv7.2 M-Current Dysfunction and Configuration Changes Manifesting as Epileptic Encephalopathies and Autistic Spectrum Disorders

by Inn-Chi Lee, Jiann-Jou Yang, Ying-Ming Liou and Swee-Hee Wong

Cells 2022, 11(5), 894; https://doi.org/10.3390/cells11050894 - 05 Mar 2022

Cited by 2 | Viewed by 3023

Abstract

KCNQ2 mutations can cause benign familial neonatal convulsions (BFNCs), epileptic encephalopathy (EE), and mild-to-profound neurodevelopmental disabilities. Mutations in the KCNQ2 selectivity filter (SF) are critical to neurodevelopmental outcomes. Three patients with neonatal EE carry de novo heterozygous KCNQ2 p.Thr287Ile, p.Gly281Glu and p.Pro285Thr, and all are followed-up in our clinics. Whole-cell patch-clamp analysis with transfected mutations was performed. The Kv7.2 in three mutations demonstrated significant current changes in the homomeric-transfected cells. The conduction curves for V_1/2, the K slope, and currents in 3 mutations were lower than those for the wild type (WT). The p.Gly281Glu had a worse conductance than the p.Thr287Ile and p.Pro285Thr, the patient compatible with p.Gly281Glu had a worse clinical outcome than patients with p.Thr287Ile and p.Pro285Thr. The p.Gly281Glu had more amino acid weight changes than the p.Gly281Glu and p.Pro285Thr. Among 5 BFNCs and 23 EE from mutations in the SF, the greater weight of the mutated protein compared with that of the WT was presumed to cause an obstacle to pore size, which is one of the most important factors in the phenotype and outcome. For the 35 mutations in the SF domain, using changes in amino acid weight between the WT and the KCNQ2 mutations to predict EE resulted in 80.0% sensitivity and 80% specificity, a positive prediction rate of 96.0%, and a negative prediction rate of 40.0% (p = 0.006, χ² (1, n = 35) = 7.56; odds ratio 16.0, 95% confidence interval, 1.50 to 170.63). The findings suggest that p.Thr287Ile, p.Gly281Glu and p.Pro285Thr are pathogenic to KCNQ2 EE. In mutations in SF, a mutated protein heavier than the WT is a factor in the Kv7.2 current and outcome. Full article

(This article belongs to the Special Issue Ca²⁺, Na⁺, and K⁺ Homeostasis and Signaling in Brain Development and Neurological Diseases)

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13 pages, 2772 KiB

Open AccessArticle

Preemptive Analgesic Effect of Intrathecal Applications of Neuroactive Steroids in a Rodent Model of Post-Surgical Pain: Evidence for the Role of T-Type Calcium Channels

by Quy L. Tat, Srdjan M. Joksimovic, Kathiresan Krishnan, Douglas F. Covey, Slobodan M. Todorovic and Vesna Jevtovic-Todorovic

Cells 2020, 9(12), 2674; https://doi.org/10.3390/cells9122674 - 12 Dec 2020

Cited by 6 | Viewed by 1580

Abstract

Preemptive management of post-incisional pain remains challenging. Here, we examined the role of preemptive use of neuroactive steroids with activity on low-voltage activated T-type Ca²⁺ channels (T-channels) and γ-aminobutyric acid A (GABA_A) receptors in the development and maintenance of post-incisional pain. We use neuroactive steroids with distinct effects on GABA_A receptors and/or T-channels: Alphaxalone (combined GABAergic agent and T-channel inhibitor), ECN (T-channel inhibitor), CDNC24 (GABAergic agent), and compared them with an established analgesic, morphine (an opioid agonist without known effect on either T-channels or GABA_A receptors). Adult female rats sustained the skin and muscle incision on the plantar surface of the right paw. We injected the agents of choice intrathecally either before or after the development of post-incisional pain. The pain development was monitored by studying mechanical hypersensitivity. Alphaxalone and ECN, but not morphine, are effective in alleviating mechanical hyperalgesia when administered preemptively whereas morphine provides dose-dependent pain relief only when administered once the pain had developed. CDNC24 on the other hand did not offer any analgesic benefit. Neuroactive steroids that inhibit T-currents—Alphaxalone and ECN—unlike morphine, are effective preemptive analgesics that may offer a promising therapeutic approach to the treatment of post-incisional pain, especially mechanical hypersensitivity. Full article

(This article belongs to the Special Issue Ca²⁺, Na⁺, and K⁺ Homeostasis and Signaling in Brain Development and Neurological Diseases)

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21 pages, 2836 KiB

Open AccessArticle

Gateways for Glutamate Neuroprotection in Parkinson’s Disease (PD): Essential Role of EAAT3 and NCX1 Revealed in an In Vitro Model of PD

by Silvia Piccirillo, Simona Magi, Alessandra Preziuso, Pasqualina Castaldo, Salvatore Amoroso and Vincenzo Lariccia

Cells 2020, 9(9), 2037; https://doi.org/10.3390/cells9092037 - 06 Sep 2020

Cited by 9 | Viewed by 3122

Abstract

Increasing evidence suggests that metabolic alterations may be etiologically linked to neurodegenerative disorders such as Parkinson’s disease (PD) and in particular empathizes the possibility of targeting mitochondrial dysfunctions to improve PD progression. Under different pathological conditions (i.e., cardiac and neuronal ischemia/reperfusion injury), we showed that supplementation of energetic substrates like glutamate exerts a protective role by preserving mitochondrial functions and enhancing ATP synthesis through a mechanism involving the Na⁺-dependent excitatory amino acid transporters (EAATs) and the Na⁺/Ca²⁺ exchanger (NCX). In this study, we investigated whether a similar approach aimed at promoting glutamate metabolism would be also beneficial against cell damage in an in vitro PD-like model. In retinoic acid (RA)-differentiated SH-SY5Y cells challenged with α-synuclein (α-syn) plus rotenone (Rot), glutamate significantly improved cell viability by increasing ATP levels, reducing oxidative damage and cytosolic and mitochondrial Ca²⁺ overload. Glutamate benefits were strikingly lost when either EAAT3 or NCX1 expression was knocked down by RNA silencing. Overall, our results open the possibility of targeting EAAT3/NCX1 functions to limit PD pathology by simultaneously favoring glutamate uptake and metabolic use in dopaminergic neurons. Full article

(This article belongs to the Special Issue Ca²⁺, Na⁺, and K⁺ Homeostasis and Signaling in Brain Development and Neurological Diseases)

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17 pages, 1724 KiB

Open AccessEditor’s ChoiceReview

Role of Microglia and Astrocytes in Alzheimer’s Disease: From Neuroinflammation to Ca²⁺ Homeostasis Dysregulation

by Giulia Di Benedetto, Chiara Burgaletto, Carlo Maria Bellanca, Antonio Munafò, Renato Bernardini and Giuseppina Cantarella

Cells 2022, 11(17), 2728; https://doi.org/10.3390/cells11172728 - 01 Sep 2022

Cited by 32 | Viewed by 6187

Abstract

Alzheimer’s disease (AD) is the most common form of dementia worldwide, with a complex, poorly understood pathogenesis. Cerebral atrophy, amyloid-β (Aβ) plaques, and neurofibrillary tangles represent the main pathological hallmarks of the AD brain. Recently, neuroinflammation has been recognized as a prominent feature of the AD brain and substantial evidence suggests that the inflammatory response modulates disease progression. Additionally, dysregulation of calcium (Ca²⁺) homeostasis represents another early factor involved in the AD pathogenesis, as intracellular Ca²⁺ concentration is essential to ensure proper cellular and neuronal functions. Although growing evidence supports the involvement of Ca²⁺ in the mechanisms of neurodegeneration-related inflammatory processes, scant data are available on its contribution in microglia and astrocytes functioning, both in health and throughout the AD continuum. Nevertheless, AD-related aberrant Ca²⁺ signalling in astrocytes and microglia is crucially involved in the mechanisms underpinning neuroinflammatory processes that, in turn, impact neuronal Ca²⁺ homeostasis and brain function. In this light, we attempted to provide an overview of the current understanding of the interactions between the glia cells-mediated inflammatory responses and the molecular mechanisms involved in Ca²⁺ homeostasis dysregulation in AD. Full article

(This article belongs to the Special Issue Ca²⁺, Na⁺, and K⁺ Homeostasis and Signaling in Brain Development and Neurological Diseases)

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Ca2+, Na+, and K+ Homeostasis and Signaling in Brain Development and Neurological Diseases

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Ca²⁺, Na⁺, and K⁺ Homeostasis and Signaling in Brain Development and Neurological Diseases