Editorial

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Open AccessEditorial

Calcium Channels and Calcium-Binding Proteins

by Sumiko Mochida

Int. J. Mol. Sci. 2023, 24(18), 14257; https://doi.org/10.3390/ijms241814257 - 19 Sep 2023

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Signals of nerve impulses are transmitted to excitatory cells to induce the action of organs via the activation of Ca²⁺ entry through voltage-gated Ca²⁺ channels (VGCC), which are classified based on their activation threshold into high- and low-voltage activated channels, expressed [...] Read more.

Signals of nerve impulses are transmitted to excitatory cells to induce the action of organs via the activation of Ca²⁺ entry through voltage-gated Ca²⁺ channels (VGCC), which are classified based on their activation threshold into high- and low-voltage activated channels, expressed specifically for each organ [...] Full article

(This article belongs to the Special Issue Calcium Channels and Calcium-Binding Proteins)

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Research

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16 pages, 2537 KiB

Open AccessArticle

Glutamate-Evoked Ca²⁺ Responses in the Rat Suprachiasmatic Nucleus: Involvement of Na⁺/K⁺-ATPase and Na⁺/Ca²⁺-Exchanger

by Pi-Cheng Cheng, Ruo-Ciao Cheng and Rong-Chi Huang

Int. J. Mol. Sci. 2023, 24(7), 6444; https://doi.org/10.3390/ijms24076444 - 29 Mar 2023

Cited by 3 | Viewed by 914

Abstract

Glutamate mediates photic entrainment of the central clock in the suprachiasmatic nucleus (SCN) by evoking intracellular Ca²⁺ signaling mechanisms. However, the detailed mechanisms of glutamate-evoked Ca²⁺ signals are not entirely clear. Here, we used a ratiometric Ca²⁺ and Na⁺ [...] Read more.

Glutamate mediates photic entrainment of the central clock in the suprachiasmatic nucleus (SCN) by evoking intracellular Ca²⁺ signaling mechanisms. However, the detailed mechanisms of glutamate-evoked Ca²⁺ signals are not entirely clear. Here, we used a ratiometric Ca²⁺ and Na⁺ imaging technique to investigate glutamate-evoked Ca²⁺ responses. The comparison of Ca²⁺ responses to glutamate (100 μM) and high (20 mM) K⁺ solution indicated slower Ca²⁺ clearance, along with rebound Ca²⁺ suppression for glutamate-evoked Ca²⁺ transients. Increasing the length of exposure time in glutamate, but not in 20 mM K⁺, slowed Ca²⁺ clearance and increased rebound Ca²⁺ suppression, a result correlated with glutamate-induced Na⁺ loads. The rebound Ca²⁺ suppression was abolished by ouabain, monensin, Na⁺-free solution, or nimodipine, suggesting an origin of activated Na⁺/K⁺-ATPase (NKA) by glutamate-induced Na⁺ loads. Ouabain or Na⁺-free solution also slowed Ca²⁺ clearance, apparently by retarding Na⁺/Ca²⁺-exchanger (NCX)-mediated Ca²⁺ extrusion. Together, our results indicated the involvement of glutamate-induced Na⁺ loads, NKA, and NCX in shaping the Ca²⁺ response to glutamate. Nevertheless, in the absence of external Na⁺ (NMDG substituted), Ca²⁺ clearance was still slower for the Ca²⁺ response to glutamate than for 20 mM K⁺, suggesting participation of additional Ca²⁺ handlers to the slower Ca²⁺ clearance under this condition. Full article

(This article belongs to the Special Issue Calcium Channels and Calcium-Binding Proteins)

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20 pages, 5862 KiB

Open AccessArticle

Spatial and Functional Crosstalk between the Mitochondrial Na⁺-Ca²⁺ Exchanger NCLX and the Sarcoplasmic Reticulum Ca²⁺ Pump SERCA in Cardiomyocytes

by Ayako Takeuchi and Satoshi Matsuoka

Int. J. Mol. Sci. 2022, 23(14), 7948; https://doi.org/10.3390/ijms23147948 - 19 Jul 2022

Cited by 6 | Viewed by 2363

Abstract

The mitochondrial Na⁺-Ca²⁺ exchanger, NCLX, was reported to supply Ca²⁺ to sarcoplasmic reticulum (SR)/endoplasmic reticulum, thereby modulating various cellular functions such as the rhythmicity of cardiomyocytes, and cellular Ca²⁺ signaling upon antigen receptor stimulation and chemotaxis in B [...] Read more.

The mitochondrial Na⁺-Ca²⁺ exchanger, NCLX, was reported to supply Ca²⁺ to sarcoplasmic reticulum (SR)/endoplasmic reticulum, thereby modulating various cellular functions such as the rhythmicity of cardiomyocytes, and cellular Ca²⁺ signaling upon antigen receptor stimulation and chemotaxis in B lymphocytes; however, there is little information on the spatial relationships of NCLX with SR Ca²⁺ handling proteins, and their physiological impact. Here we examined the issue, focusing on the interaction of NCLX with an SR Ca²⁺ pump SERCA in cardiomyocytes. A bimolecular fluorescence complementation assay using HEK293 cells revealed that the exogenously expressed NCLX was localized in close proximity to four exogenously expressed SERCA isoforms. Immunofluorescence analyses of isolated ventricular myocytes showed that the NCLX was localized to the edges of the mitochondria, forming a striped pattern. The co-localization coefficients in the super-resolution images were higher for NCLX–SERCA2, than for NCLX–ryanodine receptor and NCLX–Na⁺/K⁺ ATPase α-1 subunit, confirming the close localization of endogenous NCLX and SERCA2 in cardiomyocytes. The mathematical model implemented with the spatial and functional coupling of NCLX and SERCA well reproduced the NCLX inhibition-mediated modulations of SR Ca²⁺ reuptake in HL-1 cardiomyocytes. Taken together, these results indicated that NCLX and SERCA are spatially and functionally coupled in cardiomyocytes. Full article

(This article belongs to the Special Issue Calcium Channels and Calcium-Binding Proteins)

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13 pages, 2516 KiB

Open AccessArticle

STIM1 Controls the Focal Adhesion Dynamics and Cell Migration by Regulating SOCE in Osteosarcoma

by Yu-Shan Lin, Yi-Hsin Lin, MyHang Nguyen Thi, Shih-Chuan Hsiao and Wen-Tai Chiu

Int. J. Mol. Sci. 2022, 23(1), 162; https://doi.org/10.3390/ijms23010162 - 23 Dec 2021

Cited by 5 | Viewed by 2822

Abstract

The dysregulation of store-operated Ca²⁺ entry (SOCE) promotes cancer progression by changing Ca²⁺ levels in the cytosol or endoplasmic reticulum. Stromal interaction molecule 1 (STIM1), a component of SOCE, is upregulated in several types of cancer and responsible for cancer cell [...] Read more.

The dysregulation of store-operated Ca²⁺ entry (SOCE) promotes cancer progression by changing Ca²⁺ levels in the cytosol or endoplasmic reticulum. Stromal interaction molecule 1 (STIM1), a component of SOCE, is upregulated in several types of cancer and responsible for cancer cell migration, invasion, and metastasis. To explore the impact of STIM1-mediated SOCE on the turnover of focal adhesion (FA) and cell migration, we overexpressed the wild-type and constitutively active or dominant negative variants of STIM1 in an osteosarcoma cell line. In this study, we hypothesized that STIM1-mediated Ca²⁺ elevation may increase cell migration. We found that constitutively active STIM1 dramatically increased the Ca²⁺ influx, calpain activity, and turnover of FA proteins, such as the focal adhesion kinase (FAK), paxillin, and vinculin, which impede the cell migration ability. In contrast, dominant negative STIM1 decreased the turnover of FA proteins as its wild-type variant compared to the cells without STIM1 overexpression while promoting cell migration. These unexpected results suggest that cancer cells need an appropriate amount of Ca²⁺ to control the assembly and disassembly of focal adhesions by regulating calpain activity. On the other hand, overloaded Ca²⁺ results in excessive calpain activity, which is not beneficial for cancer metastasis. Full article

(This article belongs to the Special Issue Calcium Channels and Calcium-Binding Proteins)

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13 pages, 3043 KiB

Open AccessArticle

Age-Dependent Contributions of NMDA Receptors and L-Type Calcium Channels to Long-Term Depression in the Piriform Cortex

by Vishaal Rajani, Aida Maziar, Kwun Nok Mimi Man, Johannes W. Hell and Qi Yuan

Int. J. Mol. Sci. 2021, 22(24), 13551; https://doi.org/10.3390/ijms222413551 - 17 Dec 2021

Cited by 8 | Viewed by 2614

Abstract

In the hippocampus, the contributions of N-methyl-D-aspartate receptors (NMDARs) and L-type calcium channels (LTCCs) to neuronal transmission and synaptic plasticity change with aging, underlying calcium dysregulation and cognitive dysfunction. However, the relative contributions of NMDARs and LTCCs in other learning encoding structures during [...] Read more.

In the hippocampus, the contributions of N-methyl-D-aspartate receptors (NMDARs) and L-type calcium channels (LTCCs) to neuronal transmission and synaptic plasticity change with aging, underlying calcium dysregulation and cognitive dysfunction. However, the relative contributions of NMDARs and LTCCs in other learning encoding structures during aging are not known. The piriform cortex (PC) plays a significant role in odor associative memories, and like the hippocampus, exhibits forms of long-term synaptic plasticity. Here, we investigated the expression and contribution of NMDARs and LTCCs in long-term depression (LTD) of the PC associational fiber pathway in three cohorts of Sprague Dawley rats: neonatal (1–2 weeks), young adult (2–3 months) and aged (20–25 months). Using a combination of slice electrophysiology, Western blotting, fluorescent immunohistochemistry and confocal imaging, we observed a shift from an NMDAR to LTCC mediation of LTD in aged rats, despite no difference in the amount of LTD expression. These changes in plasticity are related to age-dependent differential receptor expression in the PC. LTCC Cav1.2 expression relative to postsynaptic density protein 95 is increased in the associational pathway of the aged PC layer Ib. Enhanced LTCC contribution in synaptic depression in the PC may contribute to altered olfactory function and learning with aging. Full article

(This article belongs to the Special Issue Calcium Channels and Calcium-Binding Proteins)

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Review

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28 pages, 2136 KiB

Open AccessReview

Regulation of Cardiac Cav1.2 Channels by Calmodulin

by Masaki Kameyama, Etsuko Minobe, Dongxue Shao, Jianjun Xu, Qinghua Gao and Liying Hao

Int. J. Mol. Sci. 2023, 24(7), 6409; https://doi.org/10.3390/ijms24076409 - 29 Mar 2023

Cited by 2 | Viewed by 2146

Abstract

Cav1.2 Ca²⁺ channels, a type of voltage-gated L-type Ca²⁺ channel, are ubiquitously expressed, and the predominant Ca²⁺ channel type, in working cardiac myocytes. Cav1.2 channels are regulated by the direct interactions with calmodulin (CaM), a Ca²⁺-binding protein that [...] Read more.

Cav1.2 Ca²⁺ channels, a type of voltage-gated L-type Ca²⁺ channel, are ubiquitously expressed, and the predominant Ca²⁺ channel type, in working cardiac myocytes. Cav1.2 channels are regulated by the direct interactions with calmodulin (CaM), a Ca²⁺-binding protein that causes Ca²⁺-dependent facilitation (CDF) and inactivation (CDI). Ca²⁺-free CaM (apoCaM) also contributes to the regulation of Cav1.2 channels. Furthermore, CaM indirectly affects channel activity by activating CaM-dependent enzymes, such as CaM-dependent protein kinase II and calcineurin (a CaM-dependent protein phosphatase). In this article, we review the recent progress in identifying the role of apoCaM in the channel ‘rundown’ phenomena and related repriming of channels, and CDF, as well as the role of Ca²⁺/CaM in CDI. In addition, the role of CaM in channel clustering is reviewed. Full article

(This article belongs to the Special Issue Calcium Channels and Calcium-Binding Proteins)

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15 pages, 4633 KiB

Open AccessReview

The Thermodynamically Expensive Contribution of Three Calcium Sources to Somatic Release of Serotonin

by Francisco F. De-Miguel

Int. J. Mol. Sci. 2022, 23(3), 1495; https://doi.org/10.3390/ijms23031495 - 28 Jan 2022

Cited by 1 | Viewed by 1911

Abstract

The soma, dendrites and axon of neurons may display calcium-dependent release of transmitters and peptides. Such release is named extrasynaptic for occurring in absence of synaptic structures. This review describes the cooperative actions of three calcium sources on somatic exocytosis. Emphasis is given [...] Read more.

The soma, dendrites and axon of neurons may display calcium-dependent release of transmitters and peptides. Such release is named extrasynaptic for occurring in absence of synaptic structures. This review describes the cooperative actions of three calcium sources on somatic exocytosis. Emphasis is given to the somatic release of serotonin by the classical leech Retzius neuron, which has allowed detailed studies on the fine steps from excitation to exocytosis. Trains of action potentials induce transmembrane calcium entry through L-type channels. For action potential frequencies above 5 Hz, summation of calcium transients on individual action potentials activates the second calcium source: ryanodine receptors produce calcium-induced calcium release. The resulting calcium tsunami activates mitochondrial ATP synthesis to fuel transport of vesicles to the plasma membrane. Serotonin that is released maintains a large-scale exocytosis by activating the third calcium source: serotonin autoreceptors coupled to phospholipase C promote IP3 production. Activated IP3 receptors in peripheral endoplasmic reticulum release calcium that promotes vesicle fusion. The Swiss-clock workings of the machinery for somatic exocytosis has a striking disadvantage. The essential calcium-releasing endoplasmic reticulum near the plasma membrane hinders the vesicle transport, drastically reducing the thermodynamic efficiency of the ATP expenses and elevating the energy cost of release. Full article

(This article belongs to the Special Issue Calcium Channels and Calcium-Binding Proteins)

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27 pages, 2384 KiB

Open AccessReview

Systematic Review of Calcium Channels and Intracellular Calcium Signaling: Relevance to Pesticide Neurotoxicity

by Carmen Costas-Ferreira and Lilian R. F. Faro

Int. J. Mol. Sci. 2021, 22(24), 13376; https://doi.org/10.3390/ijms222413376 - 13 Dec 2021

Cited by 12 | Viewed by 4681

Abstract

Pesticides of different chemical classes exert their toxic effects on the nervous system by acting on the different regulatory mechanisms of calcium (Ca²⁺) homeostasis. Pesticides have been shown to alter Ca²⁺ homeostasis, mainly by increasing its intracellular concentration above physiological [...] Read more.

Pesticides of different chemical classes exert their toxic effects on the nervous system by acting on the different regulatory mechanisms of calcium (Ca²⁺) homeostasis. Pesticides have been shown to alter Ca²⁺ homeostasis, mainly by increasing its intracellular concentration above physiological levels. The pesticide-induced Ca²⁺ overload occurs through two main mechanisms: the entry of Ca²⁺ from the extracellular medium through the different types of Ca²⁺ channels present in the plasma membrane or its release into the cytoplasm from intracellular stocks, mainly from the endoplasmic reticulum. It has also been observed that intracellular increases in the Ca²⁺ concentrations are maintained over time, because pesticides inhibit the enzymes involved in reducing its levels. Thus, the alteration of Ca²⁺ levels can lead to the activation of various signaling pathways that generate oxidative stress, neuroinflammation and, finally, neuronal death. In this review, we also discuss some proposed strategies to counteract the detrimental effects of pesticides on Ca²⁺ homeostasis. Full article

(This article belongs to the Special Issue Calcium Channels and Calcium-Binding Proteins)

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