scholarly journals The life cycle of voltage-gated Ca2+ channels in neurons: an update on the trafficking of neuronal calcium channels

2021 ◽  
Vol 5 (1) ◽  
Author(s):  
Laurent Ferron ◽  
Saloni Koshti ◽  
Gerald W. Zamponi
Keyword(s):  
Plasma Membrane ◽  
Intracellular Signaling ◽  
Critical Role ◽  
Functional Expression ◽  
Current Evidence ◽  
Precise Control ◽  
Channel Trafficking ◽  
Voltage Gated ◽  
Cellular Excitability ◽  
Ca2 Channels

Abstract Neuronal voltage-gated Ca2+ (CaV) channels play a critical role in cellular excitability, synaptic transmission, excitation–transcription coupling and activation of intracellular signaling pathways. CaV channels are multiprotein complexes and their functional expression in the plasma membrane involves finely tuned mechanisms, including forward trafficking from the endoplasmic reticulum (ER) to the plasma membrane, endocytosis and recycling. Whether genetic or acquired, alterations and defects in the trafficking of neuronal CaV channels can have severe physiological consequences. In this review, we address the current evidence concerning the regulatory mechanisms which underlie precise control of neuronal CaV channel trafficking and we discuss their potential as therapeutic targets.

Regulation and Function of WASp in Platelets by the Collagen Receptor, Glycoprotein VI

Blood ◽  
1999 ◽  
Vol 94 (12) ◽  
pp. 4166-4176 ◽  
Author(s):  
Barbara S. Gross ◽  
Jonathan I. Wilde ◽  
Lynn Quek ◽  
Helen Chapel ◽  
David L. Nelson ◽  
...  
Keyword(s):  
Tyrosine Phosphorylation ◽  
Intracellular Signaling ◽  
Kinase Inhibitors ◽  
Critical Role ◽  
Functional Expression ◽  
Apparent Difference ◽  
Gene Encoding ◽  
Glycoprotein Vi ◽  
Dense Granules ◽  
Collagen Receptor

Abstract Wiskott Aldrich syndrome (WAS) is an X-linked recessive disorder associated with abnormalities in platelets and lymphocytes giving rise to thrombocytopenia and immunodeficiency. WAS is caused by a mutation in the gene encoding the cytoskeletal protein (WASp). Despite its importance, the role of WASp in platelet function is not established. WASp was recently shown to undergo tyrosine phosphorylation in platelets after activation by collagen, suggesting that it may play a selective role in activation by the adhesion molecule. In the present study, we show that WASp is heavily tyrosine phosphorylated by a collagen-related peptide (CRP) that binds to the collagen receptor glycoprotein (GP) VI, but not to the integrin 2β1. Tyrosine phosphorylation of WASp was blocked by Src family kinase inhibitors and reduced by treatment with wortmannin and in patients with X-linked agammaglobulinemia (XLA), a condition caused by a lack of functional expression of Btk. This indicates that Src kinases, phosphatidylinositol 3-kinase (PI 3-kinase), and Btk all contribute to the regulation of tyrosine phosphorylation of WASp. The functional importance of WASp was investigated in 2 WAS brothers who show no detectable expression of WASp. Platelet aggregation and secretion from dense granules induced by CRP and thrombin was slightly enhanced in the WAS platelets relative to controls. Furthermore, there was no apparent difference in morphology in WAS platelets after stimulation by these agonists. These observations suggest that WASp does not play a critical role in intracellular signaling downstream of tyrosine kinase-linked and G protein-coupled receptors in platelets.

Functional expression of constitutive nitric oxide synthases regulated by voltage-gated Na+ and Ca2+ channels in cultured human astrocytes

Glia ◽  
2004 ◽  
Vol 46 (1) ◽  
pp. 53-62 ◽  
Author(s):  
Michiko Oka ◽  
Miyuki Wada ◽  
Akira Yamamoto ◽  
Yoshinori Itoh ◽  
Takuya Fujita
Keyword(s):  
Nitric Oxide ◽  
Functional Expression ◽  
Nitric Oxide Synthases ◽  
Voltage Gated ◽  
Human Astrocytes ◽  
Ca2 Channels

scholarly journals STIM1L is a new actin-binding splice variant involved in fast repetitive Ca2+ release

2011 ◽  
Vol 194 (2) ◽  
pp. 335-346 ◽  
Author(s):  
Basile Darbellay ◽  
Serge Arnaudeau ◽  
Charles R. Bader ◽  
Stephane Konig ◽  
Laurent Bernheim
Keyword(s):  
Plasma Membrane ◽  
Intracellular Signaling ◽  
Cell Types ◽  
Actin Binding ◽  
Slow Process ◽  
Excitable Cells ◽  
Store Depletion ◽  
Mammalian Tissues ◽  
New Protein ◽  
Ca2 Channels

Cytosolic Ca2+ signals encoded by repetitive Ca2+ releases rely on two processes to refill Ca2+ stores: Ca2+ reuptake from the cytosol and activation of a Ca2+ influx via store-operated Ca2+ entry (SOCE). However, SOCE activation is a slow process. It is delayed by >30 s after store depletion because stromal interaction molecule 1 (STIM1), the Ca2+ sensor of the intracellular stores, must form clusters and migrate to the membrane before being able to open Orai1, the plasma membrane Ca2+ channel. In this paper, we identify a new protein, STIM1L, that colocalizes with Orai1 Ca2+ channels and interacts with actin to form permanent clusters. This property allowed the immediate activation of SOCE, a characteristic required for generating repetitive Ca2+ signals with frequencies within seconds such as those frequently observed in excitable cells. STIM1L was expressed in several mammalian tissues, suggesting that many cell types rely on this Ca2+ sensor for their Ca2+ homeostasis and intracellular signaling.

Hyperglycemia alters cytoplasmic Ca2+ responses to capacitative Ca2+ influx in rat aortic smooth muscle cells

1995 ◽  
Vol 269 (6) ◽  
pp. C1482-C1488 ◽  
Author(s):  
A. A. Rivera ◽  
C. R. White ◽  
L. L. Guest ◽  
T. S. Elton ◽  
R. B. Marchase
Keyword(s):  
Smooth Muscle ◽  
Plasma Membrane ◽  
Sarcoplasmic Reticulum ◽  
Selective Inhibitor ◽  
Acetoxymethyl Ester ◽  
Aortic Smooth Muscle ◽  
Voltage Gated ◽  
Entry Pathway ◽  
Ca2 Channels ◽  
Cells Cultured

Concentrations of free cytoplasmic Ca2+ in rat aortic smooth muscle (RASM) cells were monitored using the ratiometric Ca2+ indicator fura 2-acetoxymethyl ester (AM). In RASM cells cultured in 5 mM Glc, incubation with angiotensin II, ATP, or thapsigargin [a selective inhibitor of the sarcoplasmic reticulum (SR) Ca(2+)-ATPase] depleted SR Ca2+ stores and initiated a capacitative Ca2+ influx through the plasma membrane. This influx was resistant to verapamil, a selective inhibitor of L-type voltage-gated Ca2+ channels, but was sensitive to SKF-96365, an inhibitor of the receptor-operated Ca2+ entry pathway. RASM cells cultured in 25 mM Glc exhibited a significant decrease in cytoplasmic Ca2+ responses to agonist-induced Ca2+ release from SR stores and to subsequent capacitative Ca2+ entry. In addition, the cytoplasmic response to thapsigargin-induced release of Ca2+ from the SR in hyperglycemic cells peaked more sharply than in control cells and returned to baseline more rapidly. The effects of hyperglycemia were not overcome by myo-inositol supplementation.

scholarly journals A 49-residue sequence motif in the C terminus of Nav1.9 regulates trafficking of the channel to the plasma membrane

2019 ◽  
Vol 295 (4) ◽  
pp. 1077-1090 ◽  
Author(s):  
Daria V. Sizova ◽  
Jianying Huang ◽  
Elizabeth J. Akin ◽  
Mark Estacion ◽  
Carolina Gomis-Perez ◽  
...  
Keyword(s):  
Plasma Membrane ◽  
Recombinant Expression ◽  
Critical Role ◽  
Functional Expression ◽  
Hek293 Cells ◽  
Sequence Motif ◽  
Functional Studies ◽  
C Terminus ◽  
Mechanistic Basis ◽  
Heterologous Expression Systems

Genetic and functional studies have confirmed an important role for the voltage-gated sodium channel Nav1.9 in human pain disorders. However, low functional expression of Nav1.9 in heterologous systems (e.g. in human embryonic kidney 293 (HEK293) cells) has hampered studies of its biophysical and pharmacological properties and the development of high-throughput assays for drug development targeting this channel. The mechanistic basis for the low level of Nav1.9 currents in heterologous expression systems is not understood. Here, we implemented a multidisciplinary approach to investigate the mechanisms that govern functional Nav1.9 expression. Recombinant expression of a series of Nav1.9-Nav1.7 C-terminal chimeras in HEK293 cells identified a 49-amino-acid-long motif in the C terminus of the two channels that regulates expression levels of these chimeras. We confirmed the critical role of this motif in the context of a full-length channel chimera, Nav1.9-Ct49aaNav1.7, which displayed significantly increased current density in HEK293 cells while largely retaining the characteristic Nav1.9-gating properties. High-resolution live microscopy indicated that the newly identified C-terminal motif dramatically increases the number of channels on the plasma membrane of HEK293 cells. Molecular modeling results suggested that this motif is exposed on the cytoplasmic face of the folded C terminus, where it might interact with other channel partners. These findings reveal that a 49-residue-long motif in Nav1.9 regulates channel trafficking to the plasma membrane.

Presenilin 1 Deficiency Alters the Activity of Voltage-Gated Ca2+ Channels in Cultured Cortical Neurons

2005 ◽  
Vol 94 (6) ◽  
pp. 4421-4429 ◽  
Author(s):  
David G. Cook ◽  
Xiaofan Li ◽  
Sheree D. Cherry ◽  
Angela R. Cantrell
Keyword(s):  
Cortical Neurons ◽  
Critical Role ◽  
Neuronal Firing ◽  
Voltage Gated ◽  
Voltage Dependent ◽  
Cultured Cortical Neurons ◽  
Intracellular Ca ◽  
Multiple Levels ◽  
P Type ◽  
Ca2 Channels

Presenilins 1 and 2 (PS1 and PS2, respectively) play a critical role in mediating γ-secretase cleavage of the amyloid precursor protein (APP). Numerous mutations in the presenilins are known to cause early-onset familial Alzheimer's disease (FAD). In addition, it is well established that PS1 deficiency leads to altered intracellular Ca2+ homeostasis involving endoplasmic reticulum Ca2+ stores. However, there has been little evidence suggesting Ca2+ signals from extracellular sources are influenced by PS1. Here we report that the Ca2+ currents carried by voltage-dependent Ca2+ channels are increased in PS1-deficient cortical neurons. This increase is mediated by a significant increase in the contributions of L- and P-type Ca2+ channels to the total voltage-mediated Ca2+ conductance in PS1 (−/−) neurons. In addition, chelating intracellular Ca2+ with 1,2-bis-( o-aminophenoxy)ethane- N,N,N′,N′-tetraacetic acid (BAPTA) produced an increase in Ca2+ current amplitude that was comparable to the increase caused by PS1 deficiency. In contrast to this, BAPTA had no effect on voltage-dependent Ca2+ conductances in PS1-deficient neurons. These data suggest that PS1 deficiency may influence voltage-gated Ca2+ channel function by means that involve intracellular Ca2+ signaling. These findings reveal that PS1 functions at multiple levels to regulate and stabilize intracellular Ca2+ levels that ultimately control neuronal firing behavior and influence synaptic transmission.

scholarly journals Activity of the Calcium Channel Pore Cch1 Is Dependent on a Modulatory Region of the Subunit Mid1 in Cryptococcus neoformans

2012 ◽  
Vol 12 (1) ◽  
pp. 142-150 ◽  
Author(s):  
Min-Pyo Hong ◽  
Kiem Vu ◽  
Jennifer M. Bautos ◽  
Rick Tham ◽  
Mantana Jamklang ◽  
...  
Keyword(s):  
Plasma Membrane ◽  
Cryptococcus Neoformans ◽  
Stress Responses ◽  
Fungal Pathogens ◽  
Critical Role ◽  
Functional Expression ◽  
Embryonic Cell ◽  
Channel Activity ◽  
Content Type ◽  
Channel Pore

ABSTRACTCalcium (Ca2+)-mediated signaling events in fungal pathogens such asCryptococcus neoformansare central to physiological processes, including those that mediate stress responses and promote virulence. The Cch1-Mid1 channel (CMC) represents the only high-affinity Ca2+channel in the plasma membrane of fungal cells; consequently, cryptococci cannot survive in low-Ca2+environments in the absence of CMC. Previous electrophysiological characterization revealed that Cch1, the predicted channel pore, and Mid1, a binding partner of Cch1, function as a store-operated Ca2+-selective channel gated by depletion of endoplasmic reticulum (ER) Ca2+stores. Cryptococci lacking CMC did not survive ER stress, indicating its critical role in restoring Ca2+homeostasis. Despite the requirement for Mid1 in promoting Ca2+influx via Cch1, identification of the role of Mid1 remains elusive. Here we show that the C-terminal tail of Mid1 is a modulatory region that impinges on Cch1 channel activity directly and mediates the trafficking of Mid1 to the plasma membrane. This region consists of the last 24 residues of Mid1, and the functional expression of Mid1 in a human embryonic cell line (HEK293) and inC. neoformansis dependent on this domain. Substitutions of arginine (R619A) or cysteine (C621A) in the modulatory region failed to target Mid1 to the plasma membrane and prevented CMC activity. Interestingly, loss of a predicted protein kinase C (PKC)-phosphorylated serine residue (S605A) had no effect on Mid1 trafficking but did alter the kinetics of Cch1 channel activity. Thus, establishment of Ca2+homeostasis inC. neoformansis dependent on a modulatory domain of Mid1.

scholarly journals Small-molecule CaVα1⋅CaVβ antagonist suppresses neuronal voltage-gated calcium-channel trafficking

2018 ◽  
Vol 115 (45) ◽  
pp. E10566-E10575 ◽  
Author(s):  
Xingjuan Chen ◽  
Degang Liu ◽  
Donghui Zhou ◽  
Yubing Si ◽  
David Xu ◽  
...  
Keyword(s):  
Plasma Membrane ◽  
Calcium Channel ◽  
Small Molecule ◽  
Protein Interaction ◽  
Protein Interactions ◽  
Protein Protein Interactions ◽  
Channel Trafficking ◽  
Voltage Gated ◽  
Protein Protein Interaction ◽  
Computational Screening

Extracellular calcium flow through neuronal voltage-gated CaV2.2 calcium channels converts action potential-encoded information to the release of pronociceptive neurotransmitters in the dorsal horn of the spinal cord, culminating in excitation of the postsynaptic central nociceptive neurons. The CaV2.2 channel is composed of a pore-forming α1subunit (CaVα1) that is engaged in protein–protein interactions with auxiliary α2/δ and β subunits. The high-affinity CaV2.2α1⋅CaVβ3protein–protein interaction is essential for proper trafficking of CaV2.2 channels to the plasma membrane. Here, structure-based computational screening led to small molecules that disrupt the CaV2.2α1⋅CaVβ3protein–protein interaction. The binding mode of these compounds reveals that three substituents closely mimic the side chains of hot-spot residues located on the α-helix of CaV2.2α1. Site-directed mutagenesis confirmed the critical nature of a salt-bridge interaction between the compounds and CaVβ3Arg-307. In cells, compounds decreased trafficking of CaV2.2 channels to the plasma membrane and modulated the functions of the channel. In a rodent neuropathic pain model, the compounds suppressed pain responses. Small-molecule α-helical mimetics targeting ion channel protein–protein interactions may represent a strategy for developing nonopioid analgesia and for treatment of other neurological disorders associated with calcium-channel trafficking.

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