NMDA receptor signalling controls R-type calcium channel levels at the neuronal synapse

Neuronal Signalling ◽

The Relationship ◽

AbstractRegulation of extracellular Ca++ influx by neuronal activity is a key mechanism underlying synaptic plasticity. At the neuronal synapse, activity-dependent Ca++ entry involves NMDA-type glutamate receptors (NMDARs) and voltage-gated calcium channels (VGCCs); the relationship between NMDARs and VGCCs, however, is poorly understood. Here, I report that neuronal activity specifically regulates synaptic levels of R-type VGCCs through synaptic NMDAR signalling and protein translation. This finding reveals a link between two key neuronal signalling pathways, suggesting a feedback mode for regulation of Ca++ signalling at the synapse.

Ca2+ entry through NaV channels generates submillisecond axonal Ca2+ signaling

eLife ◽

10.7554/elife.54566 ◽

2020 ◽

Vol 9 ◽

Cited By ~ 1

Author(s):

Naomi AK Hanemaaijer ◽

Marko A Popovic ◽

Xante Wilders ◽

Sara Grasman ◽

Oriol Pavón Arocas ◽

...

Keyword(s):

Calcium Channels ◽

High Speed ◽

Initial Segment ◽

Hek 293 ◽

Voltage Gated ◽

293 Cells ◽

Axonal Initial Segment ◽

Nav Channels ◽

Calcium ions (Ca2+) are essential for many cellular signaling mechanisms and enter the cytosol mostly through voltage-gated calcium channels. Here, using high-speed Ca2+ imaging up to 20 kHz in the rat layer five pyramidal neuron axon we found that activity-dependent intracellular calcium concentration ([Ca2+]i) in the axonal initial segment was only partially dependent on voltage-gated calcium channels. Instead, [Ca2+]i changes were sensitive to the specific voltage-gated sodium (NaV) channel blocker tetrodotoxin. Consistent with the conjecture that Ca2+ enters through the NaV channel pore, the optically resolved ICa in the axon initial segment overlapped with the activation kinetics of NaV channels and heterologous expression of NaV1.2 in HEK-293 cells revealed a tetrodotoxin-sensitive [Ca2+]i rise. Finally, computational simulations predicted that axonal [Ca2+]i transients reflect a 0.4% Ca2+ conductivity of NaV channels. The findings indicate that Ca2+ permeation through NaV channels provides a submillisecond rapid entry route in NaV-enriched domains of mammalian axons.

1,25-Dihydroxyvitamin D modulates L-type voltage-gated calcium channels in a subset of neurons in the developing mouse prefrontal cortex

Translational Psychiatry ◽

10.1038/s41398-019-0626-z ◽

2019 ◽

Vol 9 (1) ◽

Cited By ~ 4

Author(s):

Helen Gooch ◽

Xiaoying Cui ◽

Victor Anggono ◽

Maciej Trzaskowski ◽

Men Chee Tan ◽

...

Keyword(s):

Risk Factors ◽

Vitamin D ◽

Prefrontal Cortex ◽

Calcium Channels ◽

Brain Maturation ◽

Genome Wide Association Studies ◽

Voltage Gated ◽

Enhanced Activity ◽

Abstract Schizophrenia has been associated with a range of genetic and environmental risk factors. Here we explored a link between two risk factors that converge on a shared neurobiological pathway. Recent genome-wide association studies (GWAS) have identified risk variants in genes that code for L-type voltage-gated calcium channels (L-VGCCs), while epidemiological studies have found an increased risk of schizophrenia in those with neonatal vitamin D deficiency. The active form of vitamin D (1,25(OH)2D) is a secosteroid that rapidly modulates L-VGCCs via non-genomic mechanisms in a range of peripheral tissues, though its non-genomic effects within the brain remain largely unexplored. Here we used calcium imaging, electrophysiology and molecular biology to determine whether 1,25(OH)2D non-genomically modulated L-VGCCs in the developing prefrontal cortex, a region widely implicated in schizophrenia pathophysiology. Wide-field Ca2+ imaging revealed that physiological concentrations of 1,25(OH)2D rapidly enhanced activity-dependent somatic Ca2+ levels in a small subset of neurons in the developing PFC, termed vitamin D-responsive neurons (VDRNs). Somatic nucleated patch recordings revealed a rapid, 1,25(OH)2D-evoked increase in high-voltage-activated (HVA) Ca2+ currents. Enhanced activity-dependent Ca2+ levels were mediated by L-VGCC but not associated with any changes to Cacna1c (L-VGCC pore-forming subunit) mRNA expression. Since L-VGCC activity is critical to healthy neurodevelopment, these data suggest that suboptimal concentrations of 1,25(OH)2D could alter brain maturation through modulation of L-VGCC signalling and as such may provide a parsimonious link between epidemiologic and genetic risk factors for schizophrenia.

Trafficking of neuronal calcium channels

Neuronal Signaling ◽

10.1042/ns20160003 ◽

2017 ◽

Vol 1 (1) ◽

Cited By ~ 9

Author(s):

Norbert Weiss ◽

Gerald W. Zamponi

Keyword(s):

Plasma Membrane ◽

Calcium Channels ◽

Intracellular Calcium ◽

Dynamic Control ◽

Surface Expression ◽

Regulatory Mechanisms ◽

Signalling Pathways ◽

Physiological Functions ◽

Voltage Gated ◽

Voltage Gated Calcium Channels

Neuronal voltage-gated calcium channels (VGCCs) serve complex yet essential physiological functions via their pivotal role in translating electrical signals into intracellular calcium elevations and associated downstream signalling pathways. There are a number of regulatory mechanisms to ensure a dynamic control of the number of channels embedded in the plasma membrane, whereas alteration of the surface expression of VGCCs has been linked to various disease conditions. Here, we provide an overview of the mechanisms that control the trafficking of VGCCs to and from the plasma membrane, and discuss their implication in pathophysiological conditions and their potential as therapeutic targets.

Endothelin signalling mediates experience-dependent myelination in the CNS

eLife ◽

10.7554/elife.49493 ◽

2019 ◽

Vol 8 ◽

Cited By ~ 12

Author(s):

Matthew Swire ◽

Yuri Kotelevtsev ◽

David J Webb ◽

David A Lyons ◽

Charles ffrench-Constant

Keyword(s):

Social Isolation ◽

Neuronal Activity ◽

Signalling Pathways ◽

Endothelin Receptor ◽

Myelin Sheaths ◽

Pkc Epsilon ◽

Cns Myelination ◽

G Protein Coupled ◽

Activity Dependent ◽

Dependent Demand

Experience and changes in neuronal activity can alter CNS myelination, but the signalling pathways responsible remain poorly understood. Here we define a pathway in which endothelin, signalling through the G protein-coupled receptor endothelin receptor B and PKC epsilon, regulates the number of myelin sheaths formed by individual oligodendrocytes in mouse and zebrafish. We show that this phenotype is also observed in the prefrontal cortex of mice following social isolation, and is associated with reduced expression of vascular endothelin. Additionally, we show that increasing endothelin signalling rescues this myelination defect caused by social isolation. Together, these results indicate that the vasculature responds to changes in neuronal activity associated with experience by regulating endothelin levels, which in turn affect the myelinating capacity of oligodendrocytes. This pathway may be employed to couple the metabolic support function of myelin to activity-dependent demand and also represents a novel mechanism for adaptive myelination.

Activity-dependent phosphorylation of Ser187 is required for SNAP-25-negative modulation of neuronal voltage-gated calcium channels

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.0706211105 ◽

2007 ◽

Vol 105 (1) ◽

pp. 323-328 ◽

Cited By ~ 76

Author(s):

D. Pozzi ◽

S. Condliffe ◽

Y. Bozzi ◽

M. Chikhladze ◽

C. Grumelli ◽

...

Keyword(s):

Calcium Channels ◽

Voltage Gated ◽

Potassium channels contribute to activity-dependent scaling of dendritic inhibition

10.1101/098889 ◽

2017 ◽

Author(s):

Jeremy T. Chang ◽

Michael J. Higley

Keyword(s):

Potassium Channels ◽

Neuronal Activity ◽

Neuronal Excitability ◽

Pyramidal Neurons ◽

Critical Role ◽

Pyramidal Cells ◽

Gabaergic Inhibition ◽

Voltage Gated ◽

The Impact ◽

AbstractGABAergic inhibition plays a critical role in the regulation of neuronal activity. In the neocortex, inhibitory interneurons that target the dendrites of pyramidal cells influence both electrical and biochemical postsynaptic signaling. Voltage-gated ion channels strongly shape dendritic excitability and the integration of excitatory inputs, but their contribution to GABAergic signaling is less well understood. By combining 2-photon calcium imaging and focal GABA uncaging, we show that voltage-gated potassium channels normally suppress the GABAergic inhibition of calcium signals evoked by back-propagating action potentials in dendritic spines and shafts of cortical pyramidal neurons. Moreover, the voltage-dependent inactivation of these channels leads to enhancement of dendritic calcium inhibition following somatic spiking. Computational modeling reveals that the enhancement of calcium inhibition involves an increase in action potential depolarization coupled with the nonlinear relationship between membrane voltage and calcium channel activation. Overall, our findings highlight the interaction between intrinsic and synaptic properties and reveal a novel mechanism for the activity-dependent scaling of GABAergic inhibition.Significance StatementGABAergic inhibition potently regulates neuronal activity in the neocortex. How such inhibition interacts with the intrinsic electrophysiological properties of single neurons is not well-understood. Here we investigate the ability of voltage-gated potassium channels to regulate the impact of GABAergic inhibition in the dendrites of neocortical pyramidal neurons. Our results show that potassium channels normally reduce inhibition directed towards pyramidal neuron dendrites. However, these channels are inactivated by strong neuronal activity, leading to an enhancement of GABAergic potency and limiting the corresponding influx of dendritic calcium. Our findings illustrate a previously unappreciated relationship between neuronal excitability and GABAergic inhibition.

Effect of Divalent Cations on AMPA-Evoked Extracellular Alkaline Shifts in Rat Hippocampal Slices

Journal of Neurophysiology ◽

10.1152/jn.1999.82.4.1902 ◽

1999 ◽

Vol 82 (4) ◽

pp. 1902-1908 ◽

Cited By ~ 7

Author(s):

S. E. Smith ◽

M. Chesler

Keyword(s):

Carbonic Anhydrase ◽

Calcium Channels ◽

Divalent Cations ◽

Hippocampal Slices ◽

Strong Base ◽

Voltage Gated ◽

Alkaline Shift ◽

Ca1 Area ◽

The generation of activity-evoked extracellular alkaline shifts has been linked to the presence of external Ca2+ or Ba2+. We further investigated this dependence using pH- and Ca2+-selective microelectrodes in the CA1 area of juvenile, rat hippocampal slices. In HEPES-buffered media, alkaline transients evoked by pressure ejection of RS-α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) averaged ∼0.07 unit pH and were calculated to arise from the equivalent net addition of ∼1 mM strong base to the interstitial space. These alkaline responses were correlated with a mean decrease in [Ca2+]o of ∼300 μM. The alkalinizations were abolished reversibly in zero-Ca2+ media, becoming indiscernible at a [Ca2+]o of 117 ± 29 μM. Addition of as little as 30–50 μM Ba2+ caused the reappearance of an alkaline response. In approximately one-fourth of slices, a persistent alkaline shift of ∼0.03 unit pH was observed in zero-Ca2+ saline containing EGTA. In HEPES media, addition of 300 μM Cd2+, 100 μM Ni2+, or 100 μM nimodipine inhibited the alkaline shifts by roughly one-half, one-third, and one-third, respectively, whereas Cd+ and Ni2+ in combination fully blocked the response. In bicarbonate media, by contrast, Cd+ and Ni2+blocked only two-thirds of the response. In the presence of bicarbonate, Ni2+ caused an unexpected enhancement of the alkalinization by ∼150%. However, when the extracellular carbonic anhydrase was blocked by benzolamide, addition of Ni2+reduced the alkaline shift. These results suggested that Ni2+ partially inhibited the interstitial carbonic anhydrase and thereby increased the alkaline responses. These data indicate that an activity-dependent alkaline shift is largely dependent on the entry of Ca2+ or Ba2+ via voltage-gated calcium channels. However, sizable alkaline transients still can be generated with little or no external presence of these ions. Implications for the mechanism of the activity-dependent alkaline shift are discussed.