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Dive into the research topics where Kathryn L. Turner is active.

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Featured researches published by Kathryn L. Turner.


Journal of Cellular Physiology | 2011

Transient receptor potential canonical channels are essential for chemotactic migration of human malignant gliomas

Valerie C. Bomben; Kathryn L. Turner; Tia‐Tabitha C. Barclay; Harald Sontheimer

The majority of malignant primary brain tumors are gliomas, derived from glial cells. Grade IV gliomas, Glioblastoma multiforme, are extremely invasive and the clinical prognosis for patients is dismal. Gliomas utilize a number of proteins and pathways to infiltrate the brain parenchyma including ion channels and calcium signaling pathways. In this study, we investigated the localization and functional relevance of transient receptor potential canonical (TRPC) channels in glioma migration. We show that gliomas are attracted in a chemotactic manner to epidermal growth factor (EGF). Stimulation with EGF results in TRPC1 channel localization to the leading edge of migrating D54MG glioma cells. Additionally, TRPC1 channels co‐localize with the lipid raft proteins, caveolin‐1 and β‐cholera toxin, and biochemical assays show TRPC1 in the caveolar raft fraction of the membrane. Chemotaxis toward EGF was lost when TRPC channels were pharmacologically inhibited or by shRNA knockdown of TRPC1 channels, yet without affecting unstimulated cell motility. Moreover, lipid raft integrity was required for gliomas chemotaxis. Disruption of lipid rafts not only impaired chemotaxis but also impaired TRPC currents in whole cell recordings and decreased store‐operated calcium entry as revealed by ratiomeric calcium imaging. These data indicated that TRPC1 channel association with lipid rafts is essential for glioma chemotaxis in response to stimuli, such as EGF. J. Cell. Physiol. 226: 1879–1888, 2011.


The Journal of Neuroscience | 2013

Bradykinin-induced chemotaxis of human gliomas requires the activation of KCa3.1 and ClC-3.

Vishnu Anand Cuddapah; Kathryn L. Turner; Stefanie Seifert; Harald Sontheimer

Previous reports demonstrate that cell migration in the nervous system is associated with stereotypic changes in intracellular calcium concentration ([Ca2+]i), yet the target of these changes are essentially unknown. We examined chemotactic migration/invasion of human gliomas to study how [Ca2+]i regulates cellular movement and to identify downstream targets. Gliomas are primary brain cancers that spread exclusively within the brain, frequently migrating along blood vessels to which they are chemotactically attracted by bradykinin. Using simultaneous fura-2 Ca2+ imaging and amphotericin B perforated patch-clamp electrophysiology, we find that bradykinin raises [Ca2+]i and induces a biphasic voltage response. This voltage response is mediated by the coordinated activation of Ca2+-dependent, TRAM-34-sensitive KCa3.1 channels, and Ca2+-dependent, 4,4′-diisothiocyanato-stilbene-2,2′-disulfonic acid (DIDS)-sensitive and gluconate-sensitive Cl− channels. A significant portion of these Cl− currents can be attributed to Ca2+/calmodulin-dependent protein kinase II (CaMKII) activation of ClC-3, a voltage-gated Cl− channel/transporter, because pharmacological inhibition of CaMKII or shRNA-mediated knockdown of ClC-3 inhibited Ca2+-activated Cl− currents. Western blots show that KCa3.1 and ClC-3 are expressed in tissue samples obtained from patients diagnosed with grade IV gliomas. Both KCa3.1 and ClC-3 colocalize to the invading processes of glioma cells. Importantly, inhibition of either channel abrogates bradykinin-induced chemotaxis and reduces tumor expansion in mouse brain slices in situ. These channels should be further explored as future targets for anti-invasive drugs. Furthermore, these data elucidate a novel mechanism placing cation and anion channels downstream of ligand-mediated [Ca2+]i increases, which likely play similar roles in other migratory cells in the nervous system.


American Journal of Physiology-cell Physiology | 2012

Differential role of IK and BK potassium channels as mediators of intrinsic and extrinsic apoptotic cell death.

Michael B. McFerrin; Kathryn L. Turner; Vishnu Anand Cuddapah; Harald Sontheimer

An important event during apoptosis is regulated cell condensation known as apoptotic volume decrease (AVD). Ion channels have emerged as essential regulators of this process mediating the release of K(+) and Cl(-), which together with osmotically obliged water, results in the condensation of cell volume. Using a Grade IV human glioblastoma cell line, we examined the contribution of calcium-activated K(+) channels (K(Ca) channels) to AVD after the addition of either staurosporine (Stsp) or TNF-α-related apoptosis-inducing ligand (TRAIL) to activate the intrinsic or extrinsic pathway of apoptosis, respectively. We show that AVD can be inhibited in both pathways by high extracellular K(+) or the removal of calcium. However, BAPTA-AM was only able to inhibit Stsp-initiated AVD, whereas TRAIL-induced AVD was unaffected. Specific K(Ca) channel inhibitors revealed that Stsp-induced AVD was dependent on K(+) efflux through intermediate-conductance calcium-activated potassium (IK) channels, while TRAIL-induced AVD was mediated by large-conductance calcium-activated potassium (BK) channels. Fura-2 imaging demonstrated that Stsp induced a rapid and modest rise in calcium that was sustained over the course of AVD, while TRAIL produced no detectable rise in global intracellular calcium. Inhibition of IK channels with clotrimazole or 1-[(2-chlorophenyl) diphenylmethyl]-1H-pyrazole (TRAM-34) blocked downstream caspase-3 activation after Stsp addition, while paxilline, a specific BK channel inhibitor, had no effect. Treatment with ionomycin also induced an IK-dependent cell volume decrease. Together these results show that calcium is both necessary and sufficient to achieve volume decrease and that the two major pathways of apoptosis use unique calcium signaling to efflux K(+) through different K(Ca) channels.


Philosophical Transactions of the Royal Society B | 2014

Cl− and K+ channels and their role in primary brain tumour biology

Kathryn L. Turner; Harald Sontheimer

Profound cell volume changes occur in primary brain tumours as they proliferate, invade surrounding tissue or undergo apoptosis. These volume changes are regulated by the flux of Cl− and K+ ions and concomitant movement of water across the membrane, making ion channels pivotal to tumour biology. We discuss which specific Cl− and K+ channels are involved in defined aspects of glioma biology and how these channels are regulated. Cl− is accumulated to unusually high concentrations in gliomas by the activity of the NKCC1 transporter and serves as an osmolyte and energetic driving force for volume changes. Cell volume condensation is required as cells enter M phase of the cell cycle and this pre-mitotic condensation is caused by channel-mediated ion efflux. Similarly, Cl− and K+ channels dynamically regulate volume in invading glioma cells allowing them to adjust to small extracellular brain spaces. Finally, cell condensation is a hallmark of apoptosis and requires the concerted activation of Cl− and Ca2+-activated K+ channels. Given the frequency of mutation and high importance of ion channels in tumour biology, the opportunity exists to target them for treatment.


Cell Calcium | 2013

Calcium entry via TRPC1 channels activates chloride currents in human glioma cells.

Vishnu Anand Cuddapah; Kathryn L. Turner; Harald Sontheimer

Malignant gliomas are highly invasive brain cancers that carry a dismal prognosis. Recent studies indicate that Cl(-) channels facilitate glioma cell invasion by promoting hydrodynamic cell shape and volume changes. Here we asked how Cl(-) channels are regulated in the context of migration. Using patch-clamp recordings we show Cl(-) currents are activated by physiological increases of [Ca(2+)]i to 65 and 180nM. Cl(-) currents appear to be mediated by ClC-3, a voltage-gated, CaMKII-regulated Cl(-) channel highly expressed by glioma cells. ClC-3 channels colocalized with TRPC1 on caveolar lipid rafts on glioma cell processes. Using perforated-patch electrophysiological recordings, we demonstrate that inducible knockdown of TRPC1 expression with shRNA significantly inhibited glioma Cl(-) currents in a Ca(2+)-dependent fashion, placing Cl(-) channels under the regulation of Ca(2+) entry via TRPC1. In chemotaxis assays epidermal growth factor (EGF)-induced invasion was inhibition by TRPC1 knockdown to the same extent as pharmacological block of Cl(-) channels. Thus endogenous glioma Cl(-) channels are regulated by TRPC1. Cl(-) channels could be an important downstream target of TRPC1 in many other cells types, coupling elevations in [Ca(2+)]i to the shape and volume changes associated with migrating cells.


Glia | 2014

A proinvasive role for the Ca(2+) -activated K(+) channel KCa3.1 in malignant glioma.

Kathryn L. Turner; Avinash Honasoge; Stephanie M. Robert; Michael M. McFerrin; Harald Sontheimer

Glioblastoma multiforme are highly motile primary brain tumors. Diffuse tissue invasion hampers surgical resection leading to poor patient prognosis. Recent studies suggest that intracellular Ca2+ acts as a master regulator for cell motility and engages a number of downstream signals including Ca2+‐activated ion channels. Querying the REepository of Molecular BRAin Neoplasia DaTa (REMBRANDT), an annotated patient gene database maintained by the National Cancer Institute, we identified the intermediate conductance Ca2+‐activated K+ channels, KCa3.1, being overexpressed in 32% of glioma patients where protein expression significantly correlated with poor patient survival. To mechanistically link KCa3.1 expression to glioma invasion, we selected patient gliomas that, when propagated as xenolines in vivo, present with either high or low KCa3.1 expression. In addition, we generated U251 glioma cells that stably express an inducible knockdown shRNA to experimentally eliminate KCa3.1 expression. Subjecting these cells to a combination of in vitro and in situ invasion assays, we demonstrate that KCa3.1 expression significantly enhances glioma invasion and that either specific pharmacological inhibition with TRAM‐34 or elimination of the channel impairs invasion. Importantly, after intracranial implantation into SCID mice, ablation of KCa3.1 with inducible shRNA resulted in a significant reduction in tumor invasion into surrounding brain in vivo. These results show that KCa3.1 confers an invasive phenotype that significantly worsens a patients outlook, and suggests that KCa3.1 represents a viable therapeutic target to reduce glioma invasion. GLIA 2014;62:971–981


Neuro-oncology | 2012

The pan erbB inhibitor PD168393 enhances lysosomal dysfunction-induced apoptotic death in malignant peripheral nerve sheath tumor cells

Latika Kohli; Niroop Kaza; Nicholas J. Lavalley; Kathryn L. Turner; Stephanie J. Byer; Steven L. Carroll; Kevin A. Roth

Malignant peripheral nerve sheath tumors (MPNSTs) are rapidly progressive Schwann cell neoplasms. The erbB family of membrane tyrosine kinases has been implicated in MPNST mitogenesis and invasion and, thus, is a potential therapeutic target. However, tyrosine kinase inhibitors (TKIs) used alone have limited tumoricidal activity. Manipulating the autophagy lysosomal pathway in cells treated with cytostatic agents can promote apoptotic cell death in some cases. The goal of this study was to establish a mechanistic basis for formulating drug combinations to effectively trigger death in MPNST cells. We assessed the effects of the pan erbB inhibitor PD168393 on MPNST cell survival, caspase activation, and autophagy. PD168393 induced a cytostatic but not a cytotoxic response in MPNST cells that was accompanied by suppression of Akt and mTOR activation and increased autophagic activity. The effects of autophagy modulation on MPNST survival were then assessed following the induction of chloroquine (CQ)-induced lysosomal stress. In CQ-treated cells, suppression of autophagy was accompanied by increased caspase activation. In contrast, increased autophagy induction by inhibition of mTOR did not trigger cytotoxicity, possibly because of Akt activation. We thus hypothesized that dual targeting of mTOR and Akt by PD168393 would significantly increase cytotoxicity in cells exposed to lysosomal stress. We found that PD168393 and CQ in combination significantly increased cytotoxicity. We conclude that combinatorial therapies with erbB inhibitors and agents inducing lysosomal dysfunction may be an effective means of treating MPNSTs.


Cerebral Cortex | 2014

KCa3.1 Modulates Neuroblast Migration Along the Rostral Migratory Stream (RMS) In Vivo

Kathryn L. Turner; Harald Sontheimer


Archive | 2015

Astrocytes in Experimental Cortical Dysplasia Electrophysiological Characteristics of Reactive

A. Lyons; John J. Hablitz; Harald Sontheimer; Nikolay Karpuk; Maria Burkovetskaya; Tammy Kielian; Florian Lang; Christos Stournaras; Kathryn L. Turner; Therese Riedemann; Bernd Sutor; Stefanie Robel; Susan C. Buckingham; Jessica L. Boni; Susan L. Campbell; Niels C. Danbolt


Archive | 2015

Underlying Cell Proliferation and Migration Chloride Accumulation Drives Volume Dynamics

Christa W. Habela; Nola Jean Ernest; Amanda F. Swindall; Lorenzo Fornasari; Maria Stella Carro; Michele Mazzanti; Giuliana Pelicci; Matteo Setti; Nicoletta Savalli; Daniela Osti; Cristina Richichi; Marina Angelini; Paola Brescia; Kathryn L. Turner; Harald Sontheimer; Laurent Capelle; Gilles Huberfeld; Geneviève Chazal; Bertrand Devaux; Claudio Rivera; Marianne Labussière; Marie-Joseph Dieme; Michel Baulac; Franck Bielle; Christophe Pellegrino; Pascale Varlet

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Harald Sontheimer

University of Alabama at Birmingham

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Vishnu Anand Cuddapah

University of Alabama at Birmingham

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Florian Lang

University of Tübingen

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Avinash Honasoge

University of Alabama at Birmingham

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Carl D. Bortner

National Institutes of Health

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Christa W. Habela

University of Alabama at Birmingham

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Jessica L. Boni

University of Alabama at Birmingham

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