scholarly journals Reciprocal regulation among TRPV1 channels and phosphoi nos itide 3-kinase in response to nerve growth factor

2018 ◽  
Author(s):  
Anastasiia Stratiievska ◽  
Sara Nelson ◽  
Eric N. Senning ◽  
Jonathan D. Lautz ◽  
Stephen E.P. Smith ◽  
...  
Keyword(s):  
Total Internal Reflection ◽  
Inflammatory Mediator ◽  
Trp Channels ◽  
Pi3k Signaling ◽  
Reciprocal Regulation ◽  
Trpv1 Channels ◽  
Pi3k Activity ◽  
Trpv Channels ◽  
Receptor Neurons ◽  
Phosphoinositide 3 Kinase

AbstractAlthough it has been known for over a decade that the inflammatory mediator NGF sensitizes pain-receptor neurons through increased trafficking of TRPV1 channels to the plasma membrane, the mechanism by which this occurs remains mysterious. NGF activates phosphoinositide 3-kinase (PI3K), the enzyme that generates PIP3, and PI3K activity is required for sensitization. One tantalizing hint came from the finding that the N-terminal region of TRPV1 interacts directly with PI3K. Using 2-color total internal reflection fluorescence microscopy, we show that TRPV1 potentiates NGF-induced PI3K activity. A soluble TRPV1 fragment corresponding to the N-terminal Ankyrin repeats domain (ARD) was sufficient to produce this potentiation, indicating that allosteric regulation was involved. Further, other TRPV channels with conserved ARDs also potentiated NGF-induced PI3K activity whereas TRP channels lacking ARDs did not. Our data demonstrate a novel reciprocal regulation of PI3K signaling by the ARD of TRPV channels.

scholarly journals Reciprocal regulation among TRPV1 channels and phosphoinositide 3-kinase in response to nerve growth factor

eLife ◽  
2018 ◽  
Vol 7 ◽  
Author(s):  
Anastasiia Stratiievska ◽  
Sara Nelson ◽  
Eric N Senning ◽  
Jonathan D Lautz ◽  
Stephen EP Smith ◽  
...  
Keyword(s):  
Plasma Membrane ◽  
Total Internal Reflection ◽  
Inflammatory Mediator ◽  
Pi3k Signaling ◽  
Reciprocal Regulation ◽  
Trpv1 Channels ◽  
Pi3k Activity ◽  
Trpv Channels ◽  
Receptor Neurons ◽  
Phosphoinositide 3 Kinase

Although it has been known for over a decade that the inflammatory mediator NGF sensitizes pain-receptor neurons through increased trafficking of TRPV1 channels to the plasma membrane, the mechanism by which this occurs remains mysterious. NGF activates phosphoinositide 3-kinase (PI3K), the enzyme that generates PI(3,4)P2 and PIP3, and PI3K activity is required for sensitization. One tantalizing hint came from the finding that the N-terminal region of TRPV1 interacts directly with PI3K. Using two-color total internal reflection fluorescence microscopy, we show that TRPV1 potentiates NGF-induced PI3K activity. A soluble TRPV1 fragment corresponding to the N-terminal Ankyrin repeats domain (ARD) was sufficient to produce this potentiation, indicating that allosteric regulation was involved. Further, other TRPV channels with conserved ARDs also potentiated NGF-induced PI3K activity. Our data demonstrate a novel reciprocal regulation of PI3K signaling by the ARD of TRPV channels.

scholarly journals F-actin bundles direct the initiation and orientation of lamellipodia through adhesion-based signaling

2015 ◽  
Vol 208 (4) ◽  
pp. 443-455 ◽  
Author(s):  
Heath E. Johnson ◽  
Samantha J. King ◽  
Sreeja B. Asokan ◽  
Jeremy D. Rotty ◽  
James E. Bear ◽  
...  
Keyword(s):  
Focal Adhesion ◽  
Total Internal Reflection ◽  
Cell Shape ◽  
Platelet Derived Growth Factor ◽  
Pi3k Signaling ◽  
Actin Bundles ◽  
Signaling Dynamics ◽  
Ratiometric Imaging ◽  
Phosphoinositide 3 Kinase

Mesenchymal cells such as fibroblasts are weakly polarized and reorient directionality by a lamellipodial branching mechanism that is stabilized by phosphoinositide 3-kinase (PI3K) signaling. However, the mechanisms by which new lamellipodia are initiated and directed are unknown. Using total internal reflection fluorescence microscopy to monitor cytoskeletal and signaling dynamics in migrating cells, we show that peripheral F-actin bundles/filopodia containing fascin-1 serve as templates for formation and orientation of lamellipodia. Accordingly, modulation of fascin-1 expression tunes cell shape, quantified as the number of morphological extensions. Ratiometric imaging reveals that F-actin bundles/filopodia play both structural and signaling roles, as they prime the activation of PI3K signaling mediated by integrins and focal adhesion kinase. Depletion of fascin-1 ablated fibroblast haptotaxis on fibronectin but not platelet-derived growth factor chemotaxis. Based on these findings, we conceptualize haptotactic sensing as an exploration, with F-actin bundles directing and lamellipodia propagating the process and with signaling mediated by adhesions playing the role of integrator.

scholarly journals Migrating fibroblasts reorient directionality by a metastable, PI3K-dependent mechanism

2012 ◽  
Vol 197 (1) ◽  
pp. 105-114 ◽  
Author(s):  
Erik S. Welf ◽  
Shoeb Ahmed ◽  
Heath E. Johnson ◽  
Adam T. Melvin ◽  
Jason M. Haugh
Keyword(s):  
Cell Migration ◽  
Total Internal Reflection ◽  
Mesenchymal Cell ◽  
Lateral Spreading ◽  
Pi3k Signaling ◽  
Spatial Cues ◽  
Cell Protrusion ◽  
Pi3k Inhibition ◽  
Phosphoinositide 3 Kinase ◽  
Dependent Mechanism

Mesenchymal cell migration as exhibited by fibroblasts is distinct from amoeboid cell migration and is characterized by dynamic competition among multiple protrusions, which determines directional persistence and responses to spatial cues. Localization of phosphoinositide 3-kinase (PI3K) signaling is thought to play a broadly important role in cell motility, yet the context-dependent functions of this pathway have not been adequately elucidated. By mapping the spatiotemporal dynamics of cell protrusion/retraction and PI3K signaling monitored by total internal reflection fluorescence microscopy, we show that randomly migrating fibroblasts reorient polarity through PI3K-dependent branching and pivoting of protrusions. PI3K inhibition did not affect the initiation of newly branched protrusions, nor did it prevent protrusion induced by photoactivation of Rac. Rather, PI3K signaling increased after, not before, the onset of local protrusion and was required for the lateral spreading and stabilization of nascent branches. During chemotaxis, the branch experiencing the higher chemoattractant concentration was favored, and, thus, the cell reoriented so as to align with the external gradient.

scholarly journals Author response: Reciprocal regulation among TRPV1 channels and phosphoinositide 3-kinase in response to nerve growth factor

2018 ◽  
Author(s):  
Anastasiia Stratiievska ◽  
Sara Nelson ◽  
Eric N Senning ◽  
Jonathan D Lautz ◽  
Stephen EP Smith ◽  
...  
Keyword(s):  
Nerve Growth Factor ◽  
Growth Factor ◽  
Author Response ◽  
Reciprocal Regulation ◽  
Nerve Growth ◽  
Trpv1 Channels ◽  
Phosphoinositide 3 Kinase

scholarly journals Glycolysis fuels phosphoinositide 3-kinase signaling to bolster T cell immunity

Science ◽  
2021 ◽  
Vol 371 (6527) ◽  
pp. 405-410
Author(s):  
Ke Xu ◽  
Na Yin ◽  
Min Peng ◽  
Efstathios G. Stamatiades ◽  
Amy Shyu ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Glycolytic Enzyme ◽  
T Cell Immunity ◽  
Pi3k Signaling ◽  
Growth Factor Signaling ◽  
Atp Production ◽  
T Effector Cells ◽  
Cell Immunity ◽  
Phosphoinositide 3 Kinase

Infection triggers expansion and effector differentiation of T cells specific for microbial antigens in association with metabolic reprograming. We found that the glycolytic enzyme lactate dehydrogenase A (LDHA) is induced in CD8+ T effector cells through phosphoinositide 3-kinase (PI3K) signaling. In turn, ablation of LDHA inhibits PI3K-dependent phosphorylation of Akt and its transcription factor target Foxo1, causing defective antimicrobial immunity. LDHA deficiency cripples cellular redox control and diminishes adenosine triphosphate (ATP) production in effector T cells, resulting in attenuated PI3K signaling. Thus, nutrient metabolism and growth factor signaling are highly integrated processes, with glycolytic ATP serving as a rheostat to gauge PI3K-Akt-Foxo1 signaling in the control of T cell immunity. Such a bioenergetic mechanism for the regulation of signaling may explain the Warburg effect.

scholarly journals Irreversible temperature gating in trpv1 sheds light on channel activation

eLife ◽  
2018 ◽  
Vol 7 ◽  
Author(s):  
Ana Sánchez-Moreno ◽  
Eduardo Guevara-Hernández ◽  
Ricardo Contreras-Cervera ◽  
Gisela Rangel-Yescas ◽  
Ernesto Ladrón-de-Guevara ◽  
...  
Keyword(s):  
Trp Channels ◽  
Structural Information ◽  
Heat Absorption ◽  
Absorption Process ◽  
Open Probability ◽  
Temperature Changes ◽  
Trpv1 Channels ◽  
Channel Opening ◽  
Temperature Activation ◽  
Thermal Stimuli

Temperature-activated TRP channels or thermoTRPs are among the only proteins that can directly convert temperature changes into changes in channel open probability. In spite of a wealth of functional and structural information, the mechanism of temperature activation remains unknown. We have carefully characterized the repeated activation of TRPV1 by thermal stimuli and discovered a previously unknown inactivation process, which is irreversible. We propose that this form of gating in TRPV1 channels is a consequence of the heat absorption process that leads to channel opening.

scholarly journals Phosphoinositide 3-Kinase Binds to TRPV1 and Mediates NGF-stimulated TRPV1 Trafficking to the Plasma Membrane

2006 ◽  
Vol 128 (5) ◽  
pp. 509-522 ◽  
Author(s):  
Alexander T. Stein ◽  
Carmen A. Ufret-Vincenty ◽  
Li Hua ◽  
Luis F. Santana ◽  
Sharona E. Gordon
Keyword(s):  
Plasma Membrane ◽  
Total Internal Reflection ◽  
Specific Inhibitor ◽  
Thermal Hyperalgesia ◽  
Hek293 Cells ◽  
Drg Neurons ◽  
Excised Patches ◽  
Phosphoinositide 3 Kinase ◽  
Inside Out

Sensitization of the pain-transducing ion channel TRPV1 underlies thermal hyperalgesia by proalgesic agents such as nerve growth factor (NGF). The currently accepted model is that the NGF-mediated increase in TRPV1 function during hyperalgesia utilizes activation of phospholipase C (PLC) to cleave PIP2, proposed to tonically inhibit TRPV1. In this study, we tested the PLC model and found two lines of evidence that directly challenge its validity: (1) polylysine, a cationic phosphoinositide sequestering agent, inhibited TRPV1 instead of potentiating it, and (2) direct application of PIP2 to inside-out excised patches dramatically potentiated TRPV1. Furthermore, we show four types of experiments indicating that PI3K is physically and functionally coupled to TRPV1: (1) the p85β subunit of PI3K interacted with the N-terminal region of TRPV1 in yeast 2-hybrid experiments, (2) PI3K-p85β coimmunoprecipitated with TRPV1 from both HEK293 cells and dorsal root ganglia (DRG) neurons, (3) TRPV1 interacted with recombinant PI3K-p85 in vitro, and (4) wortmannin, a specific inhibitor of PI3K, completely abolished NGF-mediated sensitization in acutely dissociated DRG neurons. Finally, simultaneous electrophysiological and total internal reflection fluorescence (TIRF) microscopy recordings demonstrate that NGF increased the number of channels in the plasma membrane. We propose a new model for NGF-mediated hyperalgesia in which physical coupling of TRPV1 and PI3K in a signal transduction complex facilitates trafficking of TRPV1 to the plasma membrane.

scholarly journals TRPV1 channels and the progesterone receptor Sig-1R interact to regulate pain

2018 ◽  
Vol 115 (7) ◽  
pp. E1657-E1666 ◽  
Author(s):  
Miguel Ortíz-Rentería ◽  
Rebeca Juárez-Contreras ◽  
Ricardo González-Ramírez ◽  
León D. Islas ◽  
Félix Sierra-Ramírez ◽  
...  
Keyword(s):  
Transient Receptor Potential ◽  
Trp Channels ◽  
Receptor Potential ◽  
Transient Receptor Potential Vanilloid ◽  
Sigma 1 Receptor ◽  
Trpv1 Channels ◽  
Nociceptive Responses ◽  
Sigma 1 ◽  
Transient Receptor ◽  
Thermal Stimuli

The Transient Receptor Potential Vanilloid 1 (TRPV1) ion channel is expressed in nociceptors where, when activated by chemical or thermal stimuli, it functions as an important transducer of painful and itch-related stimuli. Although the interaction of TRPV1 with proteins that regulate its function has been previously explored, their modulation by chaperones has not been elucidated, as is the case for other mammalian TRP channels. Here we show that TRPV1 physically interacts with the Sigma 1 Receptor (Sig-1R), a chaperone that binds progesterone, an antagonist of Sig-1R and an important neurosteroid associated to the modulation of pain. Antagonism of Sig-1R by progesterone results in the down-regulation of TRPV1 expression in the plasma membrane of sensory neurons and, consequently, a decrease in capsaicin-induced nociceptive responses. This is observed both in males treated with a synthetic antagonist of Sig-1R and in pregnant females where progesterone levels are elevated. This constitutes a previously undescribed mechanism by which TRPV1-dependent nociception and pain can be regulated.

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