A redox-dependent thiol-switch and a Ca2+ binding site within the hinge region hierarchically depend on each other in α7β1 integrin regulation

Caliandro, Michele F.; Schmalbein, Felix; Todesca, Luca Matteo; Mörgelin, Matthias; Rezaei, Maryam; Meißner, Juliane; Siepe, Isabel; Grosche, Julius; Schwab, Albrecht; Eble, Johannes A.

doi:10.1016/j.freeradbiomed.2022.05.013

Cited by 4 publications

(2 citation statements)

References 36 publications

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“…Therefore, the combination of erlotinib with senicapoc will decrease the invasiveness of the NSCLC resistant cells and reduce the spreading of the cancer because it impairs migration. In addition to regulating NSCLC cell migration by increasing β1-integrin expression, ROS may also affect migration by directly modulating integrin function [35,36]. Taken together our findings suggest that the combined treatment with erlotinib and senicapoc might lead to a reduction of the tumor size by inducing apoptosis and to less metastatic events by impairing migration of NSCLC cancer cells (see Fig.…”

Section: Discussionmentioning

confidence: 60%

Targeting KCa3.1 channels to overcome erlotinib resistance in non-small cell lung cancer cells

Todesca,

Gerke,

Bulk

et al. 2024

Cell Death Discov.

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Almost all non-small cell lung cancer (NSCLC) patients initially responding to EGFR tyrosine kinase inhibitors (TKIs) develop acquired resistance. Since KCa3.1 channels, expressed in mitochondria and plasma membrane, regulate similar behavioral traits of NSCLC cells as EGFR, we hypothesized that their blockade contributes to overcoming EGFR-TKI resistance. Meta-analysis of microarray data revealed that KCa3.1 channel expression in erlotinib-resistant NSCLC cells correlates with that of genes of integrin and apoptosis pathways. Using erlotinib-sensitive and –resistant NSCLC cells we monitored the role of mitochondrial KCa3.1 channels in integrin signaling by studying cell-matrix adhesion with single-cell force spectroscopy. Apoptosis was quantified with fluorescence-based assays. The function of mitochondrial KCa3.1 channels in these processes was assessed by measuring the mitochondrial membrane potential and by quantifying ROS production. Functional assays were supplemented by biochemical analyses. We show that KCa3.1 channel inhibition with senicapoc in erlotinib-resistant NSCLC cells increases cell adhesion by increasing β1-integrin expression, that in turn depends on mitochondrial ROS release. Increased adhesion impairs migration of NSCLC cells in a 3D matrix. At the same time, the senicapoc-dependent ROS production induces cytochrome C release and triggers apoptosis of erlotinib-resistant NSCLC cells. Thus, KCa3.1 channel blockade overcomes EGFR-TKI resistance by inhibiting NSCLC motility and inducing apoptosis.

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Section: Discussionmentioning

confidence: 60%

Targeting KCa3.1 channels to overcome erlotinib resistance in non-small cell lung cancer cells

Todesca,

Gerke,

Bulk

et al. 2024

Cell Death Discov.

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“…Ca 2+ is necessary for nerve impulse activity and plays an important role in the mechanism determining the specific conductance changes in the nerve membrane [57]. Furthermore, a redox-dependent thiol switch might affect a nearby Ca 2+binding site [58], and it has been proposed that structural changes induced by disulfide bond formation may interfere with Ca 2+ -binding, leading to functional consequences such as enzyme inactivation [59].…”

Section: Why Does Membrane's Osmiophilia Increase In Electrically Sti...mentioning

confidence: 99%

Nerve Structure-Function: Unusual Structural Details and Unmasking of Sulfhydryl Groups by Electrical Stimulation or Asphyxia in Axon Membranes and Gap Junctions

Peracchia

2023

IJMS

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This review describes and discusses unusual axonal structural details and evidence for unmasking sulfhydryl groups (-SH) in axoplasmic membranes resulting from electrical stimulation or asphyxia. Crayfish axons contain fenestrated septa (FS) that, in phase contrast, micrographs appear as repeated striations. In the electron microscope, each septum is made of two cross-sectioned membranes containing ~55 nm pores, each occupied by a microtubule. Thin filaments, which we believe are made of kinesin, bridge the microtubule to the edge of the pore. FS are believed to play a role in axoplasmic flow. The axons also display areas in which axon and sheath glial cell plasma membranes are sharply curved and project into the axoplasm. In freeze-fractures, the protoplasmic leaflet (P-face) of the projections appears as elongated indentations containing parallel chains of particles. The sheath glial cell plasma membrane also contains particles, but they are irregularly aggregated. The axons also display areas where axonal and glial plasma membranes fuse, creating intercellular pores. In axons fixed during electrical stimulation, the plasma membrane, the outer membrane of mitochondria, membranes of other cytoplasmic organelles, and gap junctions increase in electron opacity and thickness, resulting from unmasking of sulfhydryl groups (-SH). Similar changes occur in asphyxiated nerve cords.

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Nerve Structure-Function. Unusual Structural Details and Unmasking of Sulfhydryl Groups by Electrical Stimulation or Asphyxia in Axon Membranes and Gap Junctions

Peracchia¹

2023

Preprint

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This review describes and discusses unusual axonal structural details and evidence for unmasking of sulfhydryl groups (-SH) in axoplasmic membranes resulting from electrical stimulation or asphyxia. Crayfish axons contain fenestrated septa (FS) that in phase contrast micrographs appear as repeated striations. In the electron microscope each septum is made of two cross-sectioned membranes containing ~550 Å pores, each occupied by a microtubule. Thin filaments, likely to be made of kinesin, bridge the microtubule to the edge of the pore. FS are believed to play a role in axoplasmic flow. The axons also display areas in which axon and sheath-glial cell plasma membranes are sharply curved and project into the axoplasm. In freeze-fractures, the protoplasmic leaflet (P-face) of the projections appears as elongated indentations containing parallel chains of particles. The sheath-glial cell plasma membrane also contains particles, but they are irregularly aggregated. The axons also display areas where axonal and glial plasma membranes fuse, creating intercellular pores. In axons fixed during electrical stimulation the plasma membrane, the outer membrane of mitochondria, membranes of other cytoplasmic organelles and gap junctions increase in electron opacity and thickness, resulting from unmasking of sulfhydryl groups (-SH). Similar changes occur in asphyxiated nerve cords.

show abstract

A redox-dependent thiol-switch and a Ca2+ binding site within the hinge region hierarchically depend on each other in α7β1 integrin regulation

Cited by 4 publications

References 36 publications

Targeting KCa3.1 channels to overcome erlotinib resistance in non-small cell lung cancer cells

Targeting KCa3.1 channels to overcome erlotinib resistance in non-small cell lung cancer cells

Nerve Structure-Function: Unusual Structural Details and Unmasking of Sulfhydryl Groups by Electrical Stimulation or Asphyxia in Axon Membranes and Gap Junctions

Nerve Structure-Function. Unusual Structural Details and Unmasking of Sulfhydryl Groups by Electrical Stimulation or Asphyxia in Axon Membranes and Gap Junctions

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