Calbindin regulates Kv4.1 trafficking and excitability in dentate granule cells via CaMKII-dependent phosphorylation

Kim, Kyung Ran; Jeong, Hyeon Ju; Kim, Yoonsub; Lee, Seung Yeon; Kim, Yujin; Kim, Hyun Ji; Lee, Suk Ho; Cho, Hanna; Kang, Jong Sun; Ho, Won Kyung

doi:10.1038/s12276-021-00645-4

Cited by 3 publications

(5 citation statements)

References 56 publications

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“…pCaMKII was observed among the pulled-down proteins when GST-MLC1-C-t and the FL protein were used, but not when the assay was performed with the recombinant GST-MLC1-N-t peptide ( Figure 1 G). The MLC1 GST-MLC1-C-t and FL protein also bound the serine/threonine protein phosphatase 1 (PP1) and protein phosphatase 2A (PP2A), ( Figure 1 G) with both enzymes involved in the de-phosphorylation of the CaMKII and of their target proteins [ 37 , 38 ]. In the same experiment, no binding occurred with beta dystroglycan (β-DG), a protein already found not to interact with either the MLC1 N- or C-terminal [ 19 ], and thus used as negative control.…”

Section: Resultsmentioning

confidence: 99%

“…The activation of CaMKII and the consequent CaMKII-mediated phosphorylation can strongly modulate the target protein structural organization, intracellular localization, and functionality [ 38 , 39 ]. To clarify the effects of CaMKII-mediated phosphorylation on MLC1 structural and functional properties, we generated two U251 cell lines, where the CaMKII phosphorylation site T17 was mutated into (i) alanine (T17A), a non-phosphorylatable amino acid, or (ii) aspartic acid (T17D), an amino acid mimicking protein constitutive phosphorylation.…”

Section: Resultsmentioning

confidence: 99%

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The CaMKII/MLC1 Axis Confers Ca2+-Dependence to Volume-Regulated Anion Channels (VRAC) in Astrocytes

Brignone

Lanciotti

Michelucci

et al. 2022

Cells

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Astrocytes, the main glial cells of the central nervous system, play a key role in brain volume control due to their intimate contacts with cerebral blood vessels and the expression of a distinctive equipment of proteins involved in solute/water transport. Among these is MLC1, a protein highly expressed in perivascular astrocytes and whose mutations cause megalencephalic leukoencephalopathy with subcortical cysts (MLC), an incurable leukodystrophy characterized by macrocephaly, chronic brain edema, cysts, myelin vacuolation, and astrocyte swelling. Although, in astrocytes, MLC1 mutations are known to affect the swelling-activated chloride currents (ICl,swell) mediated by the volume-regulated anion channel (VRAC), and the regulatory volume decrease, MLC1’s proper function is still unknown. By combining molecular, biochemical, proteomic, electrophysiological, and imaging techniques, we here show that MLC1 is a Ca2+/Calmodulin-dependent protein kinase II (CaMKII) target protein, whose phosphorylation, occurring in response to intracellular Ca2+ release, potentiates VRAC-mediated ICl,swell. Overall, these findings reveal that MLC1 is a Ca2+-regulated protein, linking volume regulation to Ca2+ signaling in astrocytes. This knowledge provides new insight into the MLC1 protein function and into the mechanisms controlling ion/water exchanges in the brain, which may help identify possible molecular targets for the treatment of MLC and other pathological conditions caused by astrocyte swelling and brain edema.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

The CaMKII/MLC1 Axis Confers Ca2+-Dependence to Volume-Regulated Anion Channels (VRAC) in Astrocytes

Brignone

Lanciotti

Michelucci

et al. 2022

Cells

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“…Exploring the correlation between calbindin expression and neuronal excitability, as well as ion channel expression, has been a focus in various cellular models. For example, it has been shown that dentate granule cell excitability is increased in a calbindin-D28K knockout mouse model [17], an effect attributed to a reduction in voltage-gated potassium currents. Similarly, calbindin-D28K expression in a rat beta-cell line results in a reduction of voltage-gated calcium currents [18].…”

Section: Discussionmentioning

confidence: 99%

“…Interestingly, calbindin-D28K protein expression has been correlated with distinct neuronal excitability properties. For instance, calbindin-D28K expression has been linked to alterations in neuronal action potential frequency [15, 17]. Additionally, Calbindin-D28K expression has also been associated with changes in the activity of ionic channels, such as voltage-gated calcium or potassium channels [17, 18].…”

Section: Introductionmentioning

confidence: 99%

“…Considering the correlation between changes in neuronal excitability and susceptibility to arrhythmias in cardiac pathology [27, 36] and the association of calbindin expression with modulation of neuronal excitability and ion channels [15, 17, 18], it becomes crucial to investigate whether the cardiac calbindin neuronal population possesses specific properties potentially involved in cardiac modulation. Therefore, employing a Cre-Lox mouse model that enabled precise targeting of calbindin D-28K expressing neurons, our aim is to characterize the neurochemical and electrophysiological properties of this particular cardiac neuronal population.…”

Section: Introductionmentioning

confidence: 99%

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Distinct Excitability Properties of Cardiac Calbindin Neurons: Identifying a Unique Neuronal Population

Lizot,

Bescond,

De Koninck

et al. 2024

Preprint

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The intrinsic cardiac nervous system is a complex system that plays a critical role in the regulation of cardiac physiological parameters and has been shown to contribute to cardiac arrhythmias. To date, several types of neurons with distinct neurochemical and electrophysiological phenotypes have been identified. However, no study has correlated the neurochemical phenotype to a specific electrophysiological behavior. Calbindin-D28k, a calcium binding protein, is expressed in numerous cardiac neurons. Given that changes in neuronal excitability have been associated with arrhythmia susceptibility and that calbindin expression has been associated with modulations of neuronal excitability, our objective is to assess whether the cardiac calbindin neuronal population has specific properties that could be involved in cardiac modulation and arrhythmias. By using a Cre-Lox mouse model to specifically target calbindin neurons with a fluorescent reporter, we characterized the neurochemical and the electrophysiological phenotype of this cardiac neuronal population. Calbindin neurons exhibit a specific neurochemical profile and a larger soma with shorter neurite length compared to other neurons. This was combined with a distinct electrophysiological signature characterized by a lower excitability with a predominantly phasic profile associated to a lower N-type calcium current density. These properties resemble to the cardiac neuronal remodeling observed in pathologies such as type II diabetes and heart failure. Therefore, we believe that this specific neuronal population deserves investigations in the context of these pathologies.Statements and DeclarationsThe authors have no competing interests to declare that are relevant to the content of this article.

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Calbindin-Expressing CA1 Pyramidal Neurons Encode Spatial Information More Efficiently

Ren

Lin

et al. 2023

eNeuro

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Hippocampal pyramidal neurons (PNs) are traditionally conceptualized as homogeneous population. For the past few years, cumulating evidence has revealed the structural and functional heterogeneity of hippocampal pyramidal neurons. But thein vivoneuronal firing pattern of molecularly identified pyramidal neuron subclasses is still absent. In this study, we investigated the firing patterns of hippocampal PNs based on different expression profile of Calbindin (CB) during a spatial shuttle task in free moving male mice. We found that CB+ place cells can represent spatial information more efficiently than CB- place cells, albeit lower firing rates during running epochs. Furthermore, a subset of CB+ PNs shifted their theta firing phase during rapid-eye-movement (REM) sleep states compared to running states. Although CB- PNs are more actively engaged in ripple oscillations, CB+ PNs showed stronger ripple modulation during slow-wave sleep (SWS). Our results pointed out the heterogeneity in neuronal representation between hippocampal CB+ and CB- PNs. Particularly, CB+ PNs encode spatial information more efficiently, which might be contributed by stronger afferents from the lateral entorhinal cortex to CB+ PNs.Significance StatementPyramidal neurons (PNs) in the hippocampus show heterogeneity along the longitudinal axis. But deep and superficial layer PNs are difficult to identify with traditional tetrode recordings. Combining with optogenetic tools, we were able to identify and record ephys patterns of CB+ PNs in free moving mice.We found that CB+ place cells represent spatial information more efficiently in a spatial shuttle task, with more spikes fired inside than outside of place fields, and carrying more spatial information per spike compared to CB- peers. We also found heterogeneity of neuronal firing dynamics of hippocampal PN subtypes with respect to theta and ripple oscillations.These results suggest that we take into consideration such heterogeneity of PNs in future investigations of hippocampal function.

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Calbindin regulates Kv4.1 trafficking and excitability in dentate granule cells via CaMKII-dependent phosphorylation

Cited by 3 publications

References 56 publications

The CaMKII/MLC1 Axis Confers Ca2+-Dependence to Volume-Regulated Anion Channels (VRAC) in Astrocytes

The CaMKII/MLC1 Axis Confers Ca2+-Dependence to Volume-Regulated Anion Channels (VRAC) in Astrocytes

Distinct Excitability Properties of Cardiac Calbindin Neurons: Identifying a Unique Neuronal Population

Calbindin-Expressing CA1 Pyramidal Neurons Encode Spatial Information More Efficiently

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