scholarly journals Voltage-dependent activation of Rac1 by Nav1.5 channels promotes cell migration

2019 ◽  
Author(s):  
Ming Yang ◽  
Andrew D. James ◽  
Rakesh Suman ◽  
Richard Kasprowicz ◽  
Michaela Nelson ◽  
...  
Keyword(s):  
Plasma Membrane ◽  
Cell Migration ◽  
Membrane Potential ◽  
Ion Channels ◽  
Leading Edge ◽  
Small Gtpase ◽  
Cellular Migration ◽  
Cytoskeletal Reorganization ◽  
Voltage Dependent ◽  
Electrical Signaling

AbstractIon channels can regulate the plasma membrane potential (Vm) and cell migration as a result of altered ion flux. However, the mechanism by which Vm regulates motility remains unclear. Here, we show that the Nav1.5 sodium channel carries persistent inward Na+ current which depolarizes the resting Vm at the timescale of minutes. This Nav1.5-dependent Vm depolarization increases Rac1 colocalization with phosphatidylserine, to which it is anchored at the leading edge of migrating cells, promoting Rac1 activation. A genetically-encoded FRET biosensor of Rac1 activation shows that depolarization-induced Rac1 activation results in acquisition of a motile phenotype. By identifying Nav1.5-mediated Vm depolarization as a regulator of Rac1 activation, we link ionic and electrical signaling at the plasma membrane to small GTPase-dependent cytoskeletal reorganization and cellular migration. We uncover a novel and unexpected mechanism for Rac1 activation, which fine tunes cell migration in response to ionic and/or electric field changes in the local microenvironment.

scholarly journals CD13 tethers the IQGAP1-ARF6-EFA6 complex to the plasma membrane to promote ARF6 activation, β1 integrin recycling, and cell migration

2019 ◽  
Vol 12 (579) ◽  
pp. eaav5938 ◽  
Author(s):  
Mallika Ghosh ◽  
Robin Lo ◽  
Ivan Ivic ◽  
Brian Aguilera ◽  
Veneta Qendro ◽  
...  
Keyword(s):  
Plasma Membrane ◽  
Cell Migration ◽  
Cell Adhesion ◽  
Cell Attachment ◽  
Leading Edge ◽  
Small Gtpase ◽  
Β1 Integrin ◽  
Recycling Endosomes ◽  
Cellular Processes ◽  
Early Endosomes

Cell attachment to the extracellular matrix (ECM) requires a balance between integrin internalization and recycling to the surface that is mediated by numerous proteins, emphasizing the complexity of these processes. Upon ligand binding in various cells, the β1 integrin is internalized, traffics to early endosomes, and is returned to the plasma membrane through recycling endosomes. This trafficking process depends on the cyclical activation and inactivation of small guanosine triphosphatases (GTPases) by their specific guanine exchange factors (GEFs) and their GTPase-activating proteins (GAPs). In this study, we found that the cell surface antigen CD13, a multifunctional transmembrane molecule that regulates cell-cell adhesion and receptor-mediated endocytosis, also promoted cell migration and colocalized with β1 integrin at sites of cell adhesion and at the leading edge. A lack of CD13 resulted in aberrant trafficking of internalized β1 integrin to late endosomes and its ultimate degradation. Our data indicate that CD13 promoted ARF6 GTPase activity by positioning the ARF6-GEF EFA6 at the cell membrane. In migrating cells, a complex containing phosphorylated CD13, IQGAP1, GTP-bound (active) ARF6, and EFA6 at the leading edge promoted the ARF6 GTPase cycling and cell migration. Together, our findings uncover a role for CD13 in the fundamental cellular processes of receptor recycling, regulation of small GTPase activities, cell-ECM interactions, and cell migration.

Ion channels in smooth muscle: regulators of intracellular calcium and contractility

2005 ◽  
Vol 83 (3) ◽  
pp. 215-242 ◽  
Author(s):  
Kevin S Thorneloe ◽  
Mark T Nelson
Keyword(s):  
Smooth Muscle ◽  
Plasma Membrane ◽  
Membrane Potential ◽  
Ion Channels ◽  
Feedback Mechanism ◽  
Negative Feedback Mechanism ◽  
Voltage Dependent ◽  
Intracellular Ca ◽  
Active Channels ◽  
Trisphosphate Receptor

Smooth muscle (SM) is essential to all aspects of human physiology and, therefore, key to the maintenance of life. Ion channels expressed within SM cells regulate the membrane potential, intracellular Ca2+ concentration, and contractility of SM. Excitatory ion channels function to depolarize the membrane potential. These include nonselective cation channels that allow Na+ and Ca2+ to permeate into SM cells. The nonselective cation channel family includes tonically active channels (Icat), as well as channels activated by agonists, pressure-stretch, and intracellular Ca2+ store depletion. Cl--selective channels, activated by intracellular Ca2+ or stretch, also mediate SM depolarization. Plasma membrane depolarization in SM activates voltage-dependent Ca2+ channels that demonstrate a high Ca2+ selectivity and provide influx of contractile Ca2+. Ca2+ is also released from SM intracellular Ca2+ stores of the sarcoplasmic reticulum (SR) through ryanodine and inositol trisphosphate receptor Ca2+ channels. This is part of a negative feedback mechanism limiting contraction that occurs by the Ca2+-dependent activation of large-conductance K+ channels, which hyper polarize the plasma membrane. Unlike the well-defined contractile role of SR-released Ca2+ in skeletal and cardiac muscle, the literature suggests that in SM Ca2+ released from the SR functions to limit contractility. Depolarization-activated K+ chan nels, ATP-sensitive K+ channels, and inward rectifier K+ channels also hyperpolarize SM, favouring relaxation. The expression pattern, density, and biophysical properties of ion channels vary among SM types and are key determinants of electrical activity, contractility, and SM function.Key words: smooth muscle, ion channel, membrane potential, calcium, contraction.

scholarly journals Ubiquitylation by Rab40b/Cul5 regulates Rap2 localization and activity during cell migration

2021 ◽  
Author(s):  
Emily D. Duncan ◽  
Ke-Jun Han ◽  
Margaret A. Trout ◽  
Rytis Prekeris
Keyword(s):  
Breast Cancer ◽  
Cell Migration ◽  
Cancer Cell ◽  
Breast Cancer Cell ◽  
Leading Edge ◽  
Small Gtpase ◽  
Actin Dynamics ◽  
Cancer Cell Migration ◽  
Breast Cancer Cell Migration ◽  
Cytoskeleton Dynamics

ABSTRACTCell migration is a complex process that involves coordinated changes in membrane transport, actin cytoskeleton dynamics, and extracellular matrix remodeling. Ras-like small monomeric GTPases, such as Rap2, play a key role in regulating actin cytoskeleton dynamics and cell adhesions. However, how Rap2 function, localization, and activation are regulated during cell migration is not fully understood. We previously identified the small GTPase Rab40b as a regulator of breast cancer cell migration. Rab40b contains a Suppressor of Cytokine Signaling (SOCS) box, which facilitates binding to Cullin5, a known E3 Ubiquitin Ligase component responsible for protein ubiquitylation. In this study, we show that the Rab40b/Cullin5 complex ubiquitylates Rap2. Importantly, we demonstrate that ubiquitylation regulates Rap2 activation, as well as recycling of Rap2 from the endolysosomal compartment to the lamellipodia of migrating breast cancer cells. Based on these data, we propose that Rab40b/Cullin5 ubiquitylates and regulates Rap2-dependent actin dynamics at the leading-edge, a process that is required for breast cancer cell migration and invasion.SUMMARYThe Rab40b/Cul5 complex is an emerging pro-migratory molecular machine. Duncan et al. identify the small GTPase Rap2 as a substrate of the Rab40b/Cul5 complex. They provide evidence that Rab40b/Cul5 ubiquitylates Rap2 to regulate its localization and activity during breast cancer cell migration, ultimately proposing a model by which Rap2 is targeted to the leading-edge plasma membrane to regulate actin dynamics during cell migration.

Erythrocyte Scaffolding Protein p55 Functions as An Essential Regulator of Neutrophil Polarity

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 318-318
Author(s):  
Brendan J. Quinn ◽  
Athar H. Chishti
Keyword(s):  
Plasma Membrane ◽  
Actin Polymerization ◽  
Leading Edge ◽  
Small Gtpase ◽  
Scaffolding Protein ◽  
Knockout Mouse Model ◽  
Surface Receptors ◽  
Lipid Product ◽  
Chemotactic Gradient

Abstract Erythrocyte p55 is a prototypical member of a family of scaffolding proteins known as Membrane Associated Guanylate Kinase Homologues (MAGUKs). MAGUKs are multi-domain proteins that couple signals from specialized sites at the plasma membrane to intracellular signal transduction pathways and the cytoskeleton. P55 was originally identified in the erythrocytes as part of a ternary complex with protein 4.1R and glycophorin C, providing a critical linkage between the actin cytoskeleton and the plasma membrane. Although p55 is expressed in a variety of tissues, especially hematopoietic cells, its biological function is unclear. Here, using a p55 knockout mouse model, we show that p55 plays a prominent role in the regulation of neutrophil polarization. Neutrophils are the first respondents during infection and injury, adopting a highly polarized morphology when stimulated with chemotactic factors. G proteincoupled surface receptors recognize the external chemotactic gradient and translate it into an internal gradient of signaling molecules. At the front of the cell, accumulation of the lipid product phosphatidylinositol-3,4,5-trisphosphate (PIP3), activation of the small GTPase Rac, and polymerization of F-actin stimulates a positive feedback loop promoting pseudopod formation. Here, we show that neutrophils lacking p55 form multiple transient pseudopods at the sides and back of the cell upon stimulation. P55 is required for limiting the pseudopod in the direction of chemoattractant. As a result, these neutrophils do not migrate efficiently up a chemotactic gradient in vitro. Biochemical analysis indicates that total F-actin polymerization and total Rac activation is similar between wild type and p55 knockout neutrophils. However, we found that phosphorylation of AKT, the major kinase downstream of the phosphatidylinositol 3-kinase (PI3K)-PIP3 pathway, is almost completely blocked in p55 knockout neutrophils. This finding suggests that p55 exerts its functional effect by regulating PIP3 accumulation or its localization at the membrane, which is responsible for amplification of the frontness signal and stability of the leading edge pseudopod. Consistent with this finding, the p55 null mice are significantly more susceptible to spontaneous and induced infections. Taken together, we have identified p55 as a novel mediator of the frontness signal in neutrophils that promotes polarization and efficient chemotaxis.

Ion channels and membrane potential in stimulus–secretion coupling in adrenal paraneurons

1984 ◽  
Vol 62 (5) ◽  
pp. 477-483 ◽  
Author(s):  
Daniel L. Kilpatrick
Keyword(s):  
Membrane Potential ◽  
Ion Channels ◽  
Adrenal Medulla ◽  
Nicotinic Receptor ◽  
Calcium Influx ◽  
Inhibitory Effect ◽  
Muscle Membrane ◽  
Bovine Adrenal Medulla ◽  
Voltage Dependent ◽  
Stimulus Secretion Coupling

Cultured bovine adrenal medulla cells have been shown to contain several different ion channels (Na+, Ca2+ acetylcholine receptor regulated) whose activation leads to the secretion of catecholamines. The pharmacology of these ion channels and their interactions during secretion have been examined. The mechanisms of agonist-induced calcium influx are of particular interest since this is an early obligatory event during secretion from the adrenal medulla. Data obtained on catecholamine release and 45Ca2+ uptake indicate that both voltage-dependent and voltage-independent calcium influx mechanisms operate in cultured bovine adrenal medulla cells. The significance of these results in understanding the mechanism of action of the physiological stimulus acetylcholine (Ach) will be discussed. The alkaloid channel neurotoxins D-600, batrachotoxin, veratridine, and aconitine were shown to exert a noncompetitive inhibitory effect on Ach-induced ion flux in adrenal medulla cells, presumably through an interaction with the nicotinic receptor regulated channel. Lipid-soluble neurotoxins may interact with multiple ion channels in nerve and muscle membrane.

scholarly journals GOLPH3 drives cell migration by promoting Golgi reorientation and directional trafficking to the leading edge

2016 ◽  
Vol 27 (24) ◽  
pp. 3828-3840 ◽  
Author(s):  
Mengke Xing ◽  
Marshall C. Peterman ◽  
Robert L. Davis ◽  
Karen Oegema ◽  
Andrew K. Shiau ◽  
...  
Keyword(s):  
Plasma Membrane ◽  
Cell Migration ◽  
Actin Cytoskeleton ◽  
Membrane Trafficking ◽  
Leading Edge ◽  
Invasion And Metastasis ◽  
Oncogenic Driver ◽  
Phosphatidylinositol 4 ◽  
Directional Cell Migration ◽  
Insight Into

The mechanism of directional cell migration remains an important problem, with relevance to cancer invasion and metastasis. GOLPH3 is a common oncogenic driver of human cancers, and is the first oncogene that functions at the Golgi in trafficking to the plasma membrane. Overexpression of GOLPH3 is reported to drive enhanced cell migration. Here we show that the phosphatidylinositol-4-phosphate/GOLPH3/myosin 18A/F-actin pathway that is critical for Golgi–to–plasma membrane trafficking is necessary and limiting for directional cell migration. By linking the Golgi to the actin cytoskeleton, GOLPH3 promotes reorientation of the Golgi toward the leading edge. GOLPH3 also promotes reorientation of lysosomes (but not other organelles) toward the leading edge. However, lysosome function is dispensable for migration and the GOLPH3 dependence of lysosome movement is indirect, via GOLPH3’s effect on the Golgi. By driving reorientation of the Golgi to the leading edge and driving forward trafficking, particularly to the leading edge, overexpression of GOLPH3 drives trafficking to the leading edge of the cell, which is functionally important for directional cell migration. Our identification of a novel pathway for Golgi reorientation controlled by GOLPH3 provides new insight into the mechanism of directional cell migration with important implications for understanding GOLPH3’s role in cancer.

Electrical Signaling in Neurons

The Neuron ◽  
2015 ◽  
pp. 41-62
Author(s):  
Irwin B. Levitan ◽  
Leonard K. Kaczmarek
Keyword(s):  
Plasma Membrane ◽  
Membrane Potential ◽  
Action Potentials ◽  
Sensory Information ◽  
External Stimulus ◽  
Resting Potential ◽  
Regular Pattern ◽  
Action Potential Firing ◽  
Potential Firing ◽  
Electrical Signaling

In neurons, information is carried from one part of the cell to another in the form of action potentials—large and rapidly reversible fluctuations in electrical voltage across the plasma membrane that propagate along the axon. Different neurons exhibit different patterns of action potential firing. Some neurons are normally silent; their membrane potential remains at the resting potential unless the firing of action potentials is triggered by some external stimulus, and they return to their non-firing state when the stimulus is no longer present. Many neurons exhibit more complex endogenous electrical activity, often firing action potentials in a regular pattern without an external stimulus. The electrical properties of a neuron are subject to modulation by input from the environment, including sensory information from the outside world, hormones released from other parts of the organism, and chemical and electrical signals from other neurons to which the neuron is functionally connected.

Role of Ion Channels and Transporters in Cell Migration

2012 ◽  
Vol 92 (4) ◽  
pp. 1865-1913 ◽  
Author(s):  
Albrecht Schwab ◽  
Anke Fabian ◽  
Peter J. Hanley ◽  
Christian Stock
Keyword(s):  
Cell Migration ◽  
Ion Channels ◽  
Immune Defense ◽  
The Body ◽  
Cellular Migration ◽  
Physiological Processes ◽  
Life Threatening ◽  
Health And Disease ◽  
Tumor Metastases

Cell motility is central to tissue homeostasis in health and disease, and there is hardly any cell in the body that is not motile at a given point in its life cycle. Important physiological processes intimately related to the ability of the respective cells to migrate include embryogenesis, immune defense, angiogenesis, and wound healing. On the other side, migration is associated with life-threatening pathologies such as tumor metastases and atherosclerosis. Research from the last ∼15 years revealed that ion channels and transporters are indispensable components of the cellular migration apparatus. After presenting general principles by which transport proteins affect cell migration, we will discuss systematically the role of channels and transporters involved in cell migration.

Ion Channels, Membrane Ion Currents, and the Action Potential

The Neuron ◽  
2015 ◽  
pp. 103-126
Author(s):  
Irwin B. Levitan ◽  
Leonard K. Kaczmarek
Keyword(s):  
Plasma Membrane ◽  
Membrane Potential ◽  
Ion Channels ◽  
Action Potential ◽  
Action Potentials ◽  
Firing Pattern ◽  
Ion Currents ◽  
Detailed Understanding ◽  
Neuronal Plasma Membrane ◽  
Sodium And Potassium

The flow of ions down their electrochemical gradients, through populations of ion channels in the neuronal plasma membrane, gives rise to transmembrane ion currents. It is the sum of the various currents flowing at any point in time that determines the neuron’s membrane potential. Thus the normal firing pattern of a neuron, and its response to different kinds of stimulation, can be seen as a play of interactions among the currents flowing through the different kinds of ion channels in its membrane. The activities of the sodium and potassium channels responsible for axonal action potentials are themselves dependent on voltage. Voltage clamp studies, which allow the measurement of the current flowing through these channels at fixed voltage, have provided a detailed understanding of the sequence of changes in sodium and potassium channel activity that give rise to action potentials.

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