Browse
Submit Data
Databases
API
Help

Dataset Information

17 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Ca_v2.3 channel function and Zn²⁺-induced modulation: potential mechanisms and (patho)physiological relevance.

ABSTRACT: Voltage-gated calcium channels (VGCCs) are critical for Ca²⁺ influx into all types of excitable cells, but their exact function is still poorly understood. Recent reconstruction of homology models for all human VGCCs at atomic resolution provides the opportunity for a structure-based discussion of VGCC function and novel insights into the mechanisms underlying Ca²⁺ selective flux through these channels. In the present review, we use these data as a basis to examine the structure, function, and Zn²⁺-induced modulation of Ca_v2.3 VGCCs, which mediate native R-type currents and belong to the most enigmatic members of the family. Their unique sensitivity to Zn²⁺ and the existence of multiple mechanisms of Zn²⁺ action strongly argue for a role of these channels in the modulatory action of endogenous loosely bound Zn²⁺, pools of which have been detected in a number of neuronal, endocrine, and reproductive tissues. Following a description of the different mechanisms by which Zn²⁺ has been shown or is thought to alter the function of these channels, we discuss their potential (patho)physiological relevance, taking into account what is known about the magnitude and function of extracellular Zn²⁺ signals in different tissues. While still far from complete, the picture that emerges is one where Ca_v2.3 channel expression parallels the occurrence of loosely bound Zn²⁺ pools in different tissues and where these channels may serve to translate physiological Zn²⁺ signals into changes of electrical activity and/or intracellular Ca²⁺ levels.

SUBMITTER: Neumaier F

PROVIDER: S-EPMC7583514 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Similar Datasets

AKAP5 complex facilitates purinergic modulation of vascular L-type Ca2+ channel CaV1.2.

Project description:The L-type Ca2+ channel CaV1.2 is essential for arterial myocyte excitability, gene expression and contraction. Elevations in extracellular glucose (hyperglycemia) potentiate vascular L-type Ca2+ channel via PKA, but the underlying mechanisms are unclear. Here, we find that cAMP synthesis in response to elevated glucose and the selective P2Y11 agonist NF546 is blocked by disruption of A-kinase anchoring protein 5 (AKAP5) function in arterial myocytes. Glucose and NF546-induced potentiation of L-type Ca2+ channels, vasoconstriction and decreased blood flow are prevented in AKAP5 null arterial myocytes/arteries. These responses are nucleated via the AKAP5-dependent clustering of P2Y11/ P2Y11-like receptors, AC5, PKA and CaV1.2 into nanocomplexes at the plasma membrane of human and mouse arterial myocytes. Hence, data reveal an AKAP5 signaling module that regulates L-type Ca2+ channel activity and vascular reactivity upon elevated glucose. This AKAP5-anchored nanocomplex may contribute to vascular complications during diabetic hyperglycemia.

| S-EPMC7575592 | biostudies-literature

(Patho-)physiological relevance of PINK1-dependent ubiquitin phosphorylation.

Project description:Mutations in PINK1 and PARKIN cause recessive, early-onset Parkinson's disease (PD). Together, these two proteins orchestrate a protective mitophagic response that ensures the safe disposal of damaged mitochondria. The kinase PINK1 phosphorylates ubiquitin (Ub) at the conserved residue S65, in addition to modifying the E3 ubiquitin ligase Parkin. The structural and functional consequences of Ub phosphorylation (pS65-Ub) have already been suggested from in vitro experiments, but its (patho-)physiological significance remains unknown. We have generated novel antibodies and assessed pS65-Ub signals in vitro and in cells, including primary neurons, under endogenous conditions. pS65-Ub is dependent on PINK1 kinase activity as confirmed in patient fibroblasts and postmortem brain samples harboring pathogenic mutations. We show that pS65-Ub is reversible and barely detectable under basal conditions, but rapidly induced upon mitochondrial stress in cells and amplified in the presence of functional Parkin. pS65-Ub accumulates in human brain during aging and disease in the form of cytoplasmic granules that partially overlap with mitochondrial, lysosomal, and total Ub markers. Additional studies are now warranted to further elucidate pS65-Ub functions and fully explore its potential for biomarker or therapeutic development.

| S-EPMC4576981 | biostudies-literature

Subtype-Selective Positive Modulation of KCa2.3 Channels Increases Cilia Length.

Project description:Small-conductance Ca2+-activated potassium (KCa2.x) channels are gated exclusively by intracellular Ca2+. The activation of KCa2.3 channels induces hyperpolarization, which augments Ca2+ signaling in endothelial cells. Cilia are specialized Ca2+ signaling compartments. Here, we identified compound 4 that potentiates human KCa2.3 channels selectively. The subtype selectivity of compound 4 for human KCa2.3 over rat KCa2.2a channels relies on an isoleucine residue in the HA/HB helices. Positive modulation of KCa2.3 channels by compound 4 increased flow-induced Ca2+ signaling and cilia length, while negative modulation by AP14145 reduced flow-induced Ca2+ signaling and cilia length. These findings were corroborated by the increased cilia length due to the expression of Ca2+-hypersensitive KCa2.3_G351D mutant channels and the reduced cilia length resulting from the expression of Ca2+-hyposensitive KCa2.3_I438N channels. Collectively, we were able to associate functions of KCa2.3 channels and cilia, two crucial components in the flow-induced Ca2+ signaling of endothelial cells, with potential implications in vasodilation and ciliopathic hypertension.

| S-EPMC9396613 | biostudies-literature

Molecular insights into the gating mechanisms of voltage-gated calcium channel CaV2.3.

Project description:High-voltage-activated R-type CaV2.3 channel plays pivotal roles in many physiological activities and is implicated in epilepsy, convulsions, and other neurodevelopmental impairments. Here, we determine the high-resolution cryo-electron microscopy (cryo-EM) structure of human CaV2.3 in complex with the α2δ1 and β1 subunits. The VSDII is stabilized in the resting state. Electrophysiological experiments elucidate that the VSDII is not required for channel activation, whereas the other VSDs are essential for channel opening. The intracellular gate is blocked by the W-helix. A pre-W-helix adjacent to the W-helix can significantly regulate closed-state inactivation (CSI) by modulating the association and dissociation of the W-helix with the gate. Electrostatic interactions formed between the negatively charged domain on S6II, which is exclusively conserved in the CaV2 family, and nearby regions at the alpha-interacting domain (AID) and S4-S5II helix are identified. Further functional analyses indicate that these interactions are critical for the open-state inactivation (OSI) of CaV2 channels.

| S-EPMC9889812 | biostudies-literature

Blocking Ca2+ Channel ?3 Subunit Reverses Diabetes.

Project description:Voltage-gated Ca2+ channels (Cav) are essential for pancreatic beta cell function as they mediate Ca2+ influx, which leads to insulin exocytosis. The ?3 subunit of Cav (Cav?3) has been suggested to regulate cytosolic Ca2+ ([Ca2+]i) oscillation frequency and insulin secretion under physiological conditions, but its role in diabetes is unclear. Here, we report that islets from diabetic mice show Cav?3 overexpression, altered [Ca2+]i dynamics, and impaired insulin secretion upon glucose stimulation. Consequently, in high-fat diet (HFD)-induced diabetes, Cav?3-deficient (Cav?3-/-) mice showed improved islet function and enhanced glucose tolerance. Normalization of Cav?3 expression in ob/ob islets by an antisense oligonucleotide rescued the altered [Ca2+]i dynamics and impaired insulin secretion. Importantly, transplantation of Cav?3-/- islets into the anterior chamber of the eye improved glucose tolerance in HFD-fed mice. Cav?3 overexpression in human islets also impaired insulin secretion. We thus suggest that Cav?3 may serve as a druggable target for diabetes treatment.

| S-EPMC6083041 | biostudies-literature

Cav 1.3 (CACNA1D) L-type Ca2+ channel dysfunction in CNS disorders.

Project description:Cav 1.3 belongs to the family of voltage-gated L-type Ca2+ channels and is encoded by the CACNA1D gene. Cav 1.3 channels are not only essential for cardiac pacemaking, hearing and hormone secretion but are also expressed postsynaptically in neurons, where they shape neuronal firing and plasticity. Recent findings provide evidence that human mutations in the CACNA1D gene can confer risk for the development of neuropsychiatric disease and perhaps also epilepsy. Loss of Cav 1.3 function, as shown in knock-out mouse models and by human mutations, does not result in neuropsychiatric or neurological disease symptoms, whereas their acute selective pharmacological activation results in a depressive-like behaviour in mice. Therefore it is likely that CACNA1D mutations enhancing activity may be disease relevant also in humans. Indeed, whole exome sequencing studies, originally prompted to identify mutations in primary aldosteronism, revealed de novo CACNA1D missense mutations permitting enhanced Ca2+ signalling through Cav 1.3. Remarkably, apart from primary aldosteronism, heterozygous carriers of these mutations also showed seizures and neurological abnormalities. Different missense mutations with very similar gain-of-function properties were recently reported in patients with autism spectrum disorders (ASD). These data strongly suggest that CACNA1D mutations enhancing Cav 1.3 activity confer a strong risk for - or even cause - CNS disorders, such as ASD.

| S-EPMC4823145 | biostudies-literature

In vitro and in vivo phosphorylation of the Cav2.3 voltage-gated R-type calcium channel.

Project description:During the recording of whole cell currents from stably transfected HEK-293 cells, the decline of currents carried by the recombinant human Cav2.3+β3 channel subunits is related to adenosine triphosphate (ATP) depletion after rupture of the cells. It reduces the number of functional channels and leads to a progressive shift of voltage-dependent gating to more negative potentials (Neumaier F., et al., 2018). Both effects can be counteracted by hydrolysable ATP, whose protective action is almost completely prevented by inhibition of serine/threonine but not tyrosine or lipid kinases. These findings indicate that ATP promotes phosphorylation of either the channel or an associated protein, whereas dephosphorylation during cell dialysis results in run-down. Protein phosphorylation is required for Cav2.3 channel function and could directly influence the normal features of current carried by these channels. Therefore, results from in vitro and in vivo phosphorylation of Cav2.3 are summarized to come closer to a functional analysis of structural variations in Cav2.3 splice variants.

| S-EPMC6986797 | biostudies-literature

?-Actinin-1 promotes activity of the L-type Ca2+ channel Cav 1.2.

Project description:The L-type Ca2+ channel CaV 1.2 governs gene expression, cardiac contraction, and neuronal activity. Binding of ?-actinin to the IQ motif of CaV 1.2 supports its surface localization and postsynaptic targeting in neurons. We report a bi-functional mechanism that restricts CaV 1.2 activity to its target sites. We solved separate NMR structures of the IQ motif (residues 1,646-1,664) bound to ?-actinin-1 and to apo-calmodulin (apoCaM). The CaV 1.2 K1647A and Y1649A mutations, which impair ?-actinin-1 but not apoCaM binding, but not the F1658A and K1662E mutations, which impair apoCaM but not ?-actinin-1 binding, decreased single-channel open probability, gating charge movement, and its coupling to channel opening. Thus, ?-actinin recruits CaV 1.2 to defined surface regions and simultaneously boosts its open probability so that CaV 1.2 is mostly active when appropriately localized.

| S-EPMC7049811 | biostudies-literature

L-type voltage-gated Ca2+ channel CaV1.2 regulates chondrogenesis during limb development.

Project description:All cells, including nonexcitable cells, maintain a discrete transmembrane potential (V mem), and have the capacity to modulate V mem and respond to their own and neighbors' changes in V mem Spatiotemporal variations have been described in developing embryonic tissues and in some cases have been implicated in influencing developmental processes. Yet, how such changes in V mem are converted into intracellular inputs that in turn regulate developmental gene expression and coordinate patterned tissue formation, has remained elusive. Here we document that the V mem of limb mesenchyme switches from a hyperpolarized to depolarized state during early chondrocyte differentiation. This change in V mem increases intracellular Ca2+ signaling through Ca2+ influx, via CaV1.2, 1 of L-type voltage-gated Ca2+ channels (VGCCs). We find that CaV1.2 activity is essential for chondrogenesis in the developing limbs. Pharmacological inhibition by an L-type VGCC specific blocker, or limb-specific deletion of CaV1.2, down-regulates expression of genes essential for chondrocyte differentiation, including Sox9, Col2a1, and Agc1, and thus disturbs proper cartilage formation. The Ca2+-dependent transcription factor NFATc1, which is a known major transducer of intracellular Ca2+ signaling, partly rescues Sox9 expression. These data reveal instructive roles of CaV1.2 in limb development, and more generally expand our understanding of how modulation of membrane potential is used as a mechanism of developmental regulation.

| S-EPMC6815189 | biostudies-literature

L-type Ca2+ channel-mediated Ca2+ influx adjusts neuronal mitochondrial function to physiological and pathophysiological conditions.

Project description:L-type voltage-gated Ca2+ channels (LTCCs) are implicated in neurodegenerative processes and cell death. Accordingly, LTCC antagonists have been proposed to be neuroprotective, although this view is disputed, because intentional LTCC activation can also have beneficial effects. LTCC-mediated Ca2+ influx influences mitochondrial function, which plays a crucial role in the regulation of cell viability. Hence, we investigated the effect of modulating LTCC-mediated Ca2+ influx on mitochondrial function in cultured hippocampal neurons. To activate LTCCs, neuronal activity was stimulated by increasing extracellular K+ or by application of the GABAA receptor antagonist bicuculline. The activity of LTCCs was altered by application of an agonistic (Bay K8644) or an antagonistic (isradipine) dihydropyridine. Our results demonstrated that activation of LTCC-mediated Ca2+ influx affected mitochondrial function in a bimodal manner. At moderate stimulation strength, ATP synthase activity was enhanced, an effect that involved Ca2+-induced Ca2+ release from intracellular stores. In contrast, high LTCC-mediated Ca2+ loads led to a switch in ATP synthase activity to reverse-mode operation. This effect, which required nitric oxide, helped to prevent mitochondrial depolarization and sustained increases in mitochondrial Ca2+ Our findings indicate a complex role of LTCC-mediated Ca2+ influx in the tuning and maintenance of mitochondrial function. Therefore, the use of LTCC inhibitors to protect neurons from neurodegeneration should be reconsidered carefully.

| S-EPMC7116774 | biostudies-literature