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1.
Cell ; 151(1): 111-22, 2012 Sep 28.
Article in English | MEDLINE | ID: mdl-23021219

ABSTRACT

Collapse of membrane lipid asymmetry is a hallmark of blood coagulation. TMEM16F of the TMEM16 family that includes TMEM16A/B Ca(2+)-activated Cl(-) channels (CaCCs) is linked to Scott syndrome with deficient Ca(2+)-dependent lipid scrambling. We generated TMEM16F knockout mice that exhibit bleeding defects and protection in an arterial thrombosis model associated with platelet deficiency in Ca(2+)-dependent phosphatidylserine exposure and procoagulant activity and lack a Ca(2+)-activated cation current in the platelet precursor megakaryocytes. Heterologous expression of TMEM16F generates a small-conductance Ca(2+)-activated nonselective cation (SCAN) current with subpicosiemens single-channel conductance rather than a CaCC. TMEM16F-SCAN channels permeate both monovalent and divalent cations, including Ca(2+), and exhibit synergistic gating by Ca(2+) and voltage. We further pinpointed a residue in the putative pore region important for the cation versus anion selectivity of TMEM16F-SCAN and TMEM16A-CaCC channels. This study thus identifies a Ca(2+)-activated channel permeable to Ca(2+) and critical for Ca(2+)-dependent scramblase activity during blood coagulation. PAPERFLICK:


Subject(s)
Blood Coagulation , Blood Platelets/metabolism , Calcium/metabolism , Phospholipid Transfer Proteins/metabolism , Ambystoma mexicanum , Animals , Anoctamin-1 , Anoctamins , Chloride Channels/metabolism , Hemostasis , Lipid Metabolism , Megakaryocytes/metabolism , Mice , Mice, Knockout , Oocytes/metabolism , Phospholipid Transfer Proteins/chemistry , Phospholipid Transfer Proteins/genetics , Xenopus
2.
J Biol Chem ; 294(49): 18934-18948, 2019 12 06.
Article in English | MEDLINE | ID: mdl-31659119

ABSTRACT

G protein-gated inwardly rectifying K+ (GIRK) channels belong to the inward-rectifier K+ (Kir) family, are abundantly expressed in the heart and the brain, and require that phosphatidylinositol bisphosphate is present so that intracellular channel-gating regulators such as Gßγ and Na+ ions can maintain the channel-open state. However, despite high-resolution structures (GIRK2) and a large number of functional studies, we do not have a coherent picture of how Gßγ and Na+ ions control gating of GIRK2 channels. Here, we utilized computational modeling and all-atom microsecond-scale molecular dynamics simulations to determine which gates are controlled by Na+ and Gßγ and how each regulator uses the channel domain movements to control gate transitions. We found that Na+ ions control the cytosolic gate of the channel through an anti-clockwise rotation, whereas Gßγ stabilizes the transmembrane gate in the open state through a rocking movement of the cytosolic domain. Both effects alter the way in which the channel interacts with phosphatidylinositol bisphosphate and thereby stabilizes the open states of the respective gates. These studies of GIRK channel dynamics present for the first time a comprehensive structural model that is consistent with the great body of literature on GIRK channel function.


Subject(s)
G Protein-Coupled Inwardly-Rectifying Potassium Channels/metabolism , Phosphatidylinositol 4,5-Diphosphate/metabolism , Sodium/metabolism , Animals , G Protein-Coupled Inwardly-Rectifying Potassium Channels/genetics , Humans , Molecular Dynamics Simulation
3.
Breast Cancer Res Treat ; 176(1): 181-189, 2019 Jul.
Article in English | MEDLINE | ID: mdl-30989462

ABSTRACT

PURPOSE: Older cancer patients are at increased risk of cancer-related cognitive impairment. The purpose of this study was to assess the alterations in intrinsic brain activity associated with adjuvant chemotherapy in older women with breast cancer. METHODS: Chemotherapy treatment (CT) group included sixteen women aged ≥ 60 years (range 60-82 years) with stage I-III breast cancers, who underwent both resting-state functional magnetic resonance imaging (rs-fMRI) and neuropsychological testing with NIH Toolbox for Cognition before adjuvant chemotherapy, at time point 1 (TP1), and again within 1 month after completing chemotherapy, at time point 2 (TP2). Fourteen age- and sex-matched healthy controls (HC) underwent the same assessments at matched intervals. Three voxel-wise rs-fMRI parameters: amplitude of low-frequency fluctuation (ALFF), fractional ALFF (fALFF), and regional homogeneity, were computed at each time point. The changes in rs-fMRI parameters from TP1 to TP2 for each group, the group differences in changes (the CT group vs. the HC group), and the group difference in the baseline rs-fMRI parameters were assessed. In addition, correlative analysis between the rs-fMRI parameters and neuropsychological testing scores was also performed. RESULTS: In the CT group, one brain region, which included parts of the bilateral subcallosal gyri and right anterior cingulate gyrus, displayed increased ALFF from TP1 to TP2 (cluster p-corrected = 0.024); another brain region in the left precuneus displayed decreased fALFF from TP1 to TP2 (cluster level p-corrected = 0.025). No significant changes in the rs-fMRI parameters from TP1 to TP2 were observed in the HC group. Although ALFF and fALFF alterations were observed only in the CT group, none of the between-group differences in rs-fMRI parameter changes reached statistical significance. CONCLUSIONS: Our study results of ALFF and fALFF alterations in the chemotherapy-treated women suggest that adjuvant chemotherapy may affect intrinsic brain activity in older women with breast cancer.


Subject(s)
Breast Neoplasms/complications , Breast Neoplasms/epidemiology , Chemotherapy, Adjuvant/adverse effects , Cognitive Dysfunction/epidemiology , Cognitive Dysfunction/etiology , Age Factors , Aged , Aged, 80 and over , Breast Neoplasms/drug therapy , Chemotherapy, Adjuvant/methods , Cognitive Dysfunction/diagnosis , Female , Health Care Surveys , Humans , Image Processing, Computer-Assisted , Longitudinal Studies , Magnetic Resonance Imaging , Middle Aged , Neuroimaging/methods , Pilot Projects
4.
Breast Cancer Res ; 20(1): 38, 2018 05 02.
Article in English | MEDLINE | ID: mdl-29720224

ABSTRACT

BACKGROUND: Cognitive decline is among the most feared treatment-related outcomes of older adults with cancer. The majority of older patients with breast cancer self-report cognitive problems during and after chemotherapy. Prior neuroimaging research has been performed mostly in younger patients with cancer. The purpose of this study was to evaluate longitudinal changes in brain volumes and cognition in older women with breast cancer receiving adjuvant chemotherapy. METHODS: Women aged ≥ 60 years with stage I-III breast cancer receiving adjuvant chemotherapy and age-matched and sex-matched healthy controls were enrolled. All participants underwent neuropsychological testing with the US National Institutes of Health (NIH) Toolbox for Cognition and brain magnetic resonance imaging (MRI) prior to chemotherapy, and again around one month after the last infusion of chemotherapy. Brain volumes were measured using Neuroreader™ software. Longitudinal changes in brain volumes and neuropsychological scores were analyzed utilizing linear mixed models. RESULTS: A total of 16 patients with breast cancer (mean age 67.0, SD 5.39 years) and 14 age-matched and sex-matched healthy controls (mean age 67.8, SD 5.24 years) were included: 7 patients received docetaxel and cyclophosphamide (TC) and 9 received chemotherapy regimens other than TC (non-TC). There were no significant differences in segmented brain volumes between the healthy control group and the chemotherapy group pre-chemotherapy (p > 0.05). Exploratory hypothesis generating analyses focusing on the effect of the chemotherapy regimen demonstrated that the TC group had greater volume reduction in the temporal lobe (change = - 0.26) compared to the non-TC group (change = 0.04, p for interaction = 0.02) and healthy controls (change = 0.08, p for interaction = 0.004). Similarly, the TC group had a decrease in oral reading recognition scores (change = - 6.94) compared to the non-TC group (change = - 1.21, p for interaction = 0.07) and healthy controls (change = 0.09, p for interaction = 0.02). CONCLUSIONS: There were no significant differences in segmented brain volumes between the healthy control group and the chemotherapy group; however, exploratory analyses demonstrated a reduction in both temporal lobe volume and oral reading recognition scores among patients on the TC regimen. These results suggest that different chemotherapy regimens may have differential effects on brain volume and cognition. Future, larger studies focusing on older adults with cancer on different treatment regimens are needed to confirm these findings. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01992432 . Registered on 25 November 2013. Retrospectively registered.


Subject(s)
Brain/diagnostic imaging , Breast Neoplasms/drug therapy , Chemotherapy, Adjuvant/adverse effects , Cognition/drug effects , Aged , Aged, 80 and over , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Brain/drug effects , Brain/physiopathology , Breast Neoplasms/diagnostic imaging , Breast Neoplasms/physiopathology , Female , Humans , Magnetic Resonance Imaging , Neuropsychological Tests , Pilot Projects , Treatment Outcome
5.
Breast Cancer Res Treat ; 172(2): 363-370, 2018 Nov.
Article in English | MEDLINE | ID: mdl-30088178

ABSTRACT

PURPOSE: The purpose of this study was to evaluate longitudinal changes in brain gray matter density (GMD) before and after adjuvant chemotherapy in older women with breast cancer. METHODS: We recruited 16 women aged ≥ 60 years with stage I-III breast cancers receiving adjuvant chemotherapy (CT) and 15 age- and sex-matched healthy controls (HC). The CT group underwent brain MRI and the NIH Toolbox for Cognition testing prior to adjuvant chemotherapy (time point 1, TP1) and within 1 month after chemotherapy (time point 2, TP2). The HC group underwent the same assessments at matched intervals. GMD was evaluated with the voxel-based morphometry. RESULTS: The mean age was 67 years in the CT group and 68.5 years in the HC group. There was significant GMD reduction within the chemotherapy group from TP1 to TP2. Compared to the HC group, the CT group displayed statistically significantly greater GMD reductions from TP1 to TP2 in the brain regions involving the left anterior cingulate gyrus, right insula, and left middle temporal gyrus (pFWE(family-wise error)-corrected < 0.05). The baseline GMD in left insula was positively correlated with the baseline list-sorting working memory score in the HC group (pFWE-corrected < 0.05). No correlation was observed for the changes in GMD with the changes in cognitive testing scores from TP1 to TP2 (pFWE-corrected < 0.05). CONCLUSIONS: Our findings indicate that GMD reductions were associated with adjuvant chemotherapy in older women with breast cancer. Future studies are needed to understand the clinical significance of the neuroimaging findings. This study is registered on ClinicalTrials.gov (NCT01992432).


Subject(s)
Breast Neoplasms/drug therapy , Cognition/drug effects , Gray Matter/diagnostic imaging , Memory, Short-Term/physiology , Aged , Aged, 80 and over , Breast Neoplasms/diagnostic imaging , Breast Neoplasms/physiopathology , Chemotherapy, Adjuvant/adverse effects , Female , Gray Matter/physiopathology , Humans , Magnetic Resonance Imaging , Middle Aged , Neuroimaging
6.
Brain Sci ; 13(7)2023 Jul 11.
Article in English | MEDLINE | ID: mdl-37508989

ABSTRACT

Non-small cell lung cancer (NSCLC) has a high rate of brain metastasis. The purpose of this study was to assess the differential distribution of brain metastases from primary NSCLC based on mutation status. Brain MRI scans of patients with brain metastases from primary NSCLC were retrospectively analyzed. Brain metastatic tumors were grouped according to mutation status of their primary NSCLC and the neuroimaging features of these brain metastases were analyzed. A total of 110 patients with 1386 brain metastases from primary NSCLC were included in this study. Gray matter density at the tumor center peaked at ~0.6 for all mutations. The median depths of tumors were 7.9 mm, 8.7 mm and 9.1 mm for EGFR, ALK and KRAS mutation groups, respectively (p = 0.044). Brain metastases for the EGFR mutation-positive group were more frequently located in the left cerebellum, left cuneus, left precuneus and right precentral gyrus. In the ALK mutation-positive group, brain metastases were more frequently located in the right middle occipital gyrus, right posterior cingulate, right precuneus, right precentral gyrus and right parietal lobe. In the KRAS mutation-positive patient group, brain metastases were more frequently located in the posterior left cerebellum. Our study showed differential spatial distribution of brain metastases in patients with NSCLC according to their mutation status. Information regarding distribution of brain metastases is clinically relevant as it could be helpful to guide treatment planning for targeted therapy, and for predicting prognosis.

7.
J Biol Chem ; 285(53): 41290-9, 2010 Dec 31.
Article in English | MEDLINE | ID: mdl-21044958

ABSTRACT

G protein-activated inwardly rectifying potassium (GIRK or Kir3) channels are directly gated by the ßγ subunits of G proteins and contribute to inhibitory neurotransmitter signaling pathways. Paradoxically, volatile anesthetics such as halothane inhibit these channels. We find that neuronal Kir3 currents are highly sensitive to inhibition by halothane. Given that Kir3 currents result from increased Gßγ available to the channels, we asked whether reducing available Gßγ to the channel would adversely affect halothane inhibition. Remarkably, scavenging Gßγ using the C-terminal domain of ß-adrenergic receptor kinase (cßARK) resulted in channel activation by halothane. Consistent with this effect, channel mutants that impair Gßγ activation were also activated by halothane. A single residue, phenylalanine 192, occupies the putative Gßγ gate of neuronal Kir3.2 channels. Mutation of Phe-192 at the gate to other residues rendered the channel non-responsive, either activated or inhibited by halothane. These data indicated that halothane predominantly interferes with Gßγ-mediated Kir3 currents, such as those functioning during inhibitory synaptic activity. Our report identifies the molecular correlate for anesthetic inhibition of Kir3 channels and highlights the significance of these effects in modulating neurotransmitter-mediated inhibitory signaling.


Subject(s)
G Protein-Coupled Inwardly-Rectifying Potassium Channels/chemistry , GTP-Binding Protein beta Subunits/metabolism , GTP-Binding Protein gamma Subunits/metabolism , Anesthetics , Animals , Binding Sites , Cell Line , Halothane/chemistry , Hippocampus/metabolism , Humans , Neurotransmitter Agents/chemistry , Oocytes/metabolism , Patch-Clamp Techniques , Protein Structure, Tertiary , Xenopus , beta-Adrenergic Receptor Kinases/metabolism
8.
Proc Natl Acad Sci U S A ; 105(20): 7188-93, 2008 May 20.
Article in English | MEDLINE | ID: mdl-18480266

ABSTRACT

The alpha9beta1 integrin accelerates cell migration through binding of spermidine/spermine acetyltransferase (SSAT) to the alpha9 cytoplasmic domain. We now show that SSAT enhances alpha9-mediated migration specifically through catabolism of spermidine and/or spermine. Because spermine and spermidine are effective blockers of K(+) ion efflux through inward-rectifier K(+) (Kir) channels, we examined the involvement of Kir channels in this pathway. The Kir channel inhibitor, barium, or knockdown of a single subunit, Kir4.2, specifically inhibited alpha9-dependent cell migration. alpha9beta1 and Kir4.2 colocalized in focal adhesions at the leading edge of migrating cells and inhibition or knockdown of Kir4.2 caused reduced persistence and an increased number of lamellipodial extensions in cells migrating on an alpha9beta1 ligand. These results identify a pathway through which the alpha9 integrin subunit stimulates cell migration by localized polyamine catabolism and modulation of Kir channel function.


Subject(s)
Gene Expression Regulation , Integrins/metabolism , Polyamines/metabolism , Potassium Channels/metabolism , Animals , CHO Cells , Cell Movement , Cricetinae , Cricetulus , Fibroblasts/metabolism , Ligands , Mice , Polyamines/chemistry , Potassium Channels, Inwardly Rectifying/chemistry , Spermidine/chemistry , Spermine/chemistry
9.
Front Oncol ; 11: 621088, 2021.
Article in English | MEDLINE | ID: mdl-33747933

ABSTRACT

Background: Brain metastases are associated with poor survival. Molecular genetic testing informs on targeted therapy and survival. The purpose of this study was to perform a MR imaging-based radiomic analysis of brain metastases from non-small cell lung cancer (NSCLC) to identify radiomic features that were important for predicting survival duration. Methods: We retrospectively identified our study cohort via an institutional database search for patients with brain metastases from EGFR, ALK, and/or KRAS mutation-positive NSCLC. We segmented the brain metastatic tumors on the brain MR images, extracted radiomic features, constructed radiomic scores from significant radiomic features based on multivariate Cox regression analysis (p < 0.05), and built predictive models for survival duration. Result: Of the 110 patients in the cohort (mean age 57.51 ± 12.32 years; range: 22-85 years, M:F = 37:73), 75, 26, and 15 had NSCLC with EGFR, ALK, and KRAS mutations, respectively. Predictive modeling of survival duration using both clinical and radiomic features yielded areas under the receiver operative characteristic curve of 0.977, 0.905, and 0.947 for the EGFR, ALK, and KRAS mutation-positive groups, respectively. Radiomic scores enabled the separation of each mutation-positive group into two subgroups with significantly different survival durations, i.e., shorter vs. longer duration when comparing to the median survival duration of the group. Conclusion: Our data supports the use of radiomic scores, based on MR imaging of brain metastases from NSCLC, as non-invasive biomarkers for survival duration. Future research with a larger sample size and external cohorts is needed to validate our results.

10.
Magn Reson Imaging ; 69: 49-56, 2020 06.
Article in English | MEDLINE | ID: mdl-32179095

ABSTRACT

Lung cancer metastases comprise most of all brain metastases in adults and most brain metastases are diagnosed by magnetic resonance (MR) scans. The purpose of this study was to conduct an MR imaging-based radiomic analysis of brain metastatic lesions from patients with primary lung cancer to classify mutational status of the metastatic disease. We retrospectively identified lung cancer patients with brain metastases treated at our institution between 2009 and 2017 who underwent genotype testing of their primary lung cancer. Brain MR Images were used for segmentation of enhancing tumors and peritumoral edema, and for radiomic feature extraction. The most relevant radiomic features were identified and used with clinical data to train random forest classifiers to classify the mutation status. Of 110 patients in the study cohort (mean age 57.51 ± 12.32 years; M: F = 37:73), 75 had an EGFR mutation, 21 had an ALK translocation, and 15 had a KRAS mutation. One patient had both ALK translocation and EGFR mutation. Majority of radiomic features most relevant for mutation classification were textural. Model building using both radiomic features and clinical data yielded more accurate classifications than using either alone. For classification of EGFR, ALK, and KRAS mutation status, the model built with both radiomic features and clinical data resulted in area-under-the-curve (AUC) values based on cross-validation of 0.912, 0.915, and 0.985, respectively. Our study demonstrated that MR imaging-based radiomic analysis of brain metastases in patients with primary lung cancer may be used to classify mutation status. This approach may be useful for devising treatment strategies and informing prognosis.


Subject(s)
Brain Neoplasms/diagnostic imaging , Brain Neoplasms/secondary , DNA Mutational Analysis , Lung Neoplasms/diagnostic imaging , Magnetic Resonance Imaging , Adult , Aged , Algorithms , Anaplastic Lymphoma Kinase/genetics , Area Under Curve , ErbB Receptors/genetics , Female , Humans , Male , Middle Aged , Mutation , Neoplasm Metastasis/pathology , Prognosis , Proto-Oncogene Proteins p21(ras)/genetics , Retrospective Studies
11.
J Geriatr Oncol ; 11(2): 290-296, 2020 03.
Article in English | MEDLINE | ID: mdl-31685415

ABSTRACT

OBJECTIVE: We aimed to use diffusion tensor imaging (DTI) to detect alterations in white matter microstructure in older patients with breast cancer receiving chemotherapy. METHODS: We recruited women age ≥60 years with stage I-III breast cancer (chemotherapy [CT] group; n = 19) to undergo two study assessments: at baseline and within one month after chemotherapy. Each assessment consisted of a brain magnetic resonance imaging scan with DTI and neuropsychological (NP) testing using the National Institutes of Health (NIH) Toolbox Cognition Battery. An age- and sex-matched group of healthy controls (HC, n = 14) underwent the same assessments at matched intervals. Four DTI parameters (fractional anisotropy [FA], mean diffusivity [MD], axial diffusivity [AD], and radial diffusivity [RD]) were calculated and correlated with NP testing scores. RESULTS: For CT group but not HCs, we detected statistically significant increases in MD and RD in the genu of the corpus callosum from time point 1 to time point 2 at p < 0.01, effect size:0.3655 and 0.3173, and 95% confidence interval: from 0.1490 to 0.5821, and from 0.1554 to 0.4792, for MD and RD respectively. AD values increased for the CT group and decreased for the HC group over time, resulting in significant between-group differences (p = 0.0056, effect size:1.0215, 95% confidence interval: from 0.2773 to 1.7657). There were no significant correlations between DTI parameters and NP scores (p > 0.05). CONCLUSIONS: We identified alterations in white matter microstructures in older women with breast cancer undergoing chemotherapy. These findings may potentially serve as neuroimaging biomarkers for identifying cognitive impairment in older adults with cancer.


Subject(s)
Diffusion Tensor Imaging , White Matter , Aged , Aging , Brain/diagnostic imaging , Female , Humans , Longitudinal Studies , White Matter/diagnostic imaging
12.
Neuron ; 37(6): 963-75, 2003 Mar 27.
Article in English | MEDLINE | ID: mdl-12670425

ABSTRACT

KCNQ channels belong to a family of potassium ion channels with crucial roles in physiology and disease. Heteromers of KCNQ2/3 subunits constitute the neuronal M channels. Inhibition of M currents, by pathways that stimulate phospholipase C activity, controls excitability throughout the nervous system. Here we show that a common feature of all KCNQ channels is their activation by the signaling membrane phospholipid phosphatidylinositol-bis-phosphate (PIP(2)). We show that wortmannin, at concentrations that prevent recovery from receptor-mediated inhibition of M currents, blocks PIP(2) replenishment to the cell surface. Moreover, we identify a C-terminal histidine residue, immediately proximal to the plasma membrane, mutation of which renders M channels less sensitive to PIP(2) and more sensitive to receptor-mediated inhibition. Finally, native or recombinant channels inhibited by muscarinic agonists can be activated by PIP(2). Our data strongly suggest that PIP(2) acts as a membrane-diffusible second messenger to regulate directly the activity of KCNQ currents.


Subject(s)
Neurons/physiology , Phosphatidylinositol 4,5-Diphosphate/pharmacology , Potassium Channels/physiology , Receptors, Muscarinic/physiology , Androstadienes/pharmacology , Animals , Bradykinin/pharmacology , CHO Cells , Cells, Cultured , Cricetinae , Electric Conductivity , Enzyme Inhibitors/pharmacology , Female , Hydrolysis , KCNQ2 Potassium Channel , KCNQ3 Potassium Channel , Microscopy, Confocal , Mutation , Patch-Clamp Techniques , Phosphatidylinositol 4,5-Diphosphate/metabolism , Phosphoinositide-3 Kinase Inhibitors , Potassium Channels/genetics , Potassium Channels, Voltage-Gated , Rats , Rats, Sprague-Dawley , Receptor, Muscarinic M1 , Recombinant Proteins , Second Messenger Systems , Signal Transduction , Superior Cervical Ganglion/cytology , Tetraethylammonium/pharmacology , Transfection , Wortmannin , Xenopus laevis
13.
Neuron ; 34(6): 933-44, 2002 Jun 13.
Article in English | MEDLINE | ID: mdl-12086641

ABSTRACT

Inwardly rectifying K(+) (Kir) channels are important regulators of resting membrane potential and cell excitability. The activity of Kir channels is critically dependent on the integrity of channel interactions with phosphatidylinositol 4,5-bisphosphate (PIP(2)). Here we identify and characterize channel-PIP(2) interactions that are conserved among Kir family members. We find basic residues that interact with PIP(2), two of which have been associated with Andersen's and Bartter's syndromes. We show that several naturally occurring mutants decrease channel-PIP(2) interactions, leading to disease.


Subject(s)
Conserved Sequence/genetics , Phosphatidylinositol 4,5-Diphosphate/metabolism , Potassium Channels, Inwardly Rectifying/genetics , Potassium Channels, Inwardly Rectifying/metabolism , Amino Acid Sequence/genetics , Animals , Bartter Syndrome/genetics , Bartter Syndrome/metabolism , Female , Glycogen Storage Disease Type IV/genetics , Glycogen Storage Disease Type IV/metabolism , Ion Channel Gating/genetics , Membrane Potentials/genetics , Molecular Sequence Data , Mutation/genetics , Oocytes/metabolism , Xenopus laevis
14.
Magn Reson Imaging ; 54: 218-224, 2018 12.
Article in English | MEDLINE | ID: mdl-30076946

ABSTRACT

As the number of older adults in the U.S. increases, so too will the incidence of cancer and cancer-related cognitive impairment (CRCI). However, the exact underlying biological mechanism for CRCI is not yet well understood. We utilized susceptibility-weighted imaging with quantitative susceptibility mapping, a non-invasive MRI-based technique, to assess longitudinal iron deposition in subcortical gray matter structures and evaluate its association with cognitive performance in women age 60+ with breast cancer receiving adjuvant chemotherapy and age-matched women without breast cancer as controls. Brain MRI scans and neurocognitive scores from the NIH Toolbox for Cognition were obtained before chemotherapy (time point 1) and within one month after the last infusion of chemotherapy for the patients and at matched intervals for the controls (time point 2). There were 14 patients age 60+ with breast cancer (mean age 66.3 ±â€¯5.3 years) and 13 controls (mean age 68.2 ±â€¯6.1 years) included in this study. Brain iron increased as age increased. There were no significant between- or within- group differences in neurocognitive scores or iron deposition at time point 1 or between time points 1 and 2 (p > 0.01). However, there was a negative correlation between iron in the globus pallidus and the fluid cognition composite scores in the control group at time point 1 (r = -0.71; p < 0.01), but not in the chemotherapy group. Baseline iron in the putamen was negatively associated with changes in the oral reading recognition scores in the control group (r = 0.74, p < 0.01), but not in the chemotherapy group. Brain iron assessment did not indicate cancer or chemotherapy related short-term differences, yet some associations with cognition were observed. Studies with larger samples and longer follow-up intervals are warranted.


Subject(s)
Brain/diagnostic imaging , Breast Neoplasms/diagnostic imaging , Chemotherapy, Adjuvant , Iron/metabolism , Aged , Aged, 80 and over , Brain Stem/diagnostic imaging , Breast Neoplasms/drug therapy , Cognition , Cognitive Dysfunction/diagnostic imaging , Cognitive Dysfunction/etiology , Female , Globus Pallidus/diagnostic imaging , Humans , Magnetic Resonance Imaging , Middle Aged , Neuroimaging , Neuropsychological Tests , Pilot Projects , Putamen/diagnostic imaging
15.
Sci STKE ; 2003(194): PE32, 2003 Aug 05.
Article in English | MEDLINE | ID: mdl-12902568

ABSTRACT

Dissociation of the heterotrimeric GTP-binding protein (G protein) betagamma subunits from the alpha subunit is a prerequisite step in the ability of these proteins to signal to downstream effectors. There is evidence that ions such as Na+ and Cl- can facilitate this dissociation. Interestingly, for KACh, the first known effector for Gbetagamma, intracellular Na+ can also activate the channel independently of Gbetagamma. Both Gbetagamma and Na+ strengthen channel interactions with the membrane phospholipid phosphatidylinositol 4,5-bisphosphate (PIP2), an event thought to be essential in opening the channel. PIP2 interacts with channel regions that form a binding pocket proximal to the transmembrane domains and is likely to exert a tangential, pulling force to mechanically open a gate at the cytoplasmic face of the channel pore. The tangential force generated by channel-PIP2 interactions is the likely force behind gating in all inwardly rectifying K+ channels. The gate opens when the lower part of the pore-lining transmembrane alpha helix pivots around a glycine residue in the middle of the helix. This mechanism of channel gating is conserved among K+ channels from bacteria to mammals and may represent a common mechanism for K+ channel gating.


Subject(s)
GTP-Binding Protein beta Subunits , GTP-Binding Protein gamma Subunits , Heterotrimeric GTP-Binding Proteins/physiology , Potassium Channels, Inwardly Rectifying , Potassium Channels/physiology , Signal Transduction/physiology , G Protein-Coupled Inwardly-Rectifying Potassium Channels , Heterotrimeric GTP-Binding Proteins/chemistry , Heterotrimeric GTP-Binding Proteins/metabolism , Potassium Channels/chemistry , Potassium Channels/metabolism
16.
Elife ; 2: e00508, 2013 Sep 10.
Article in English | MEDLINE | ID: mdl-24040509

ABSTRACT

Mammalian pluripotent stem cells (PSCs) represent an important venue for understanding basic principles regulating tissue-specific differentiation and discovering new tools that may facilitate clinical applications. Mechanisms that direct neural differentiation of PSCs involve growth factor signaling and transcription regulation. However, it is unknown whether and how electrical activity influences this process. Here we report a high throughput imaging-based screen, which uncovers that selamectin, an anti-helminthic therapeutic compound with reported activity on invertebrate glutamate-gated chloride channels, promotes neural differentiation of PSCs. We show that selamectin's pro-neurogenic activity is mediated by γ2-containing GABAA receptors in subsets of neural rosette progenitors, accompanied by increased proneural and lineage-specific transcription factor expression and cell cycle exit. In vivo, selamectin promotes neurogenesis in developing zebrafish. Our results establish a chemical screening platform that reveals activity-dependent neural differentiation from PSCs. Compounds identified in this and future screening might prove therapeutically beneficial for treating neurodevelopmental or neurodegenerative disorders. DOI:http://dx.doi.org/10.7554/eLife.00508.001.


Subject(s)
Cell Differentiation , Neurons/cytology , Pluripotent Stem Cells/cytology , Animals , Cell Lineage , Cells, Cultured , High-Throughput Screening Assays , Ivermectin/analogs & derivatives , Ivermectin/pharmacology , Mice , Neurons/drug effects , Receptors, GABA-A/drug effects
18.
Channels (Austin) ; 2(1): 19-33, 2008.
Article in English | MEDLINE | ID: mdl-18690051

ABSTRACT

Phosphatidylinositol bisphosphate (PIP(2)) is the most abundant phosphoinositide in the plasma membrane of cells and its interaction with many ion channel proteins has proven to be a critical factor enabling ion channel gating. All members of the inwardly rectifying potassium (Kir) channel family depend on PIP(2) for their activity, displaying distinct affinities and stereospecificities of interaction with the phosphoinositide. Here, we explored the stoichiometry of Kir channels with PIP(2). We first showed that PIP(2) regulated the activity of Kir3.4 channels mainly by altering their bursting behavior. Detailed burst analysis indicates that the channels assumed up to four open states and a connectivity of four between open and closed states depending on the available PIP(2) levels. Moreover, by controlling the number of PIP(2)-sensitive subunits in the stoichiometry of a tetrameric Kir2.1 channel, we showed that characteristic channel activity was obtained when at least two wild-type subunits were present. Our studies support a kinetic model for gating of Kir channels by PIP(2), where each of the four open states corresponds to the channel activated by one to four PIP(2) molecules.


Subject(s)
Phosphatidylinositol Phosphates/chemistry , Animals , Cell Membrane/metabolism , Dimerization , Enzyme Inhibitors/pharmacology , Female , Humans , Ion Channel Gating , Kinetics , Models, Biological , Models, Chemical , Mutation , Potassium Channels, Inwardly Rectifying/chemistry , Time Factors , Xenopus
19.
Pflugers Arch ; 455(1): 83-95, 2007 Oct.
Article in English | MEDLINE | ID: mdl-17520276

ABSTRACT

Phosphoinositides, such as phosphatidylinositol-bisphosphate (PIP(2)), control the activity of many ion channels in yet undefined ways. Inwardly, rectifying potassium (Kir) channels were the first shown to be dependent on direct interactions with phosphoinositides. Alterations in channel-PIP(2) interactions affect Kir single-channel gating behavior. Aberrations in channel-PIP(2) interactions can lead to human disease. As the activity of all Kir channels depends on their interactions with phosphoinositides, future research will aim to understand the molecular events that occur from phosphoinositide binding to channel gating. The determination of atomic resolution structures for several mammalian and bacterial Kir channels provides great promise towards this goal. We have mapped onto the three-dimensional channel structure the position of basic residues identified through mutagenesis studies that contribute to the sensitivity of a Kir channel to PIP(2). The localization of these putative PIP(2)-interacting residues relative to the channel's permeation pathway has given rise to a testable model, which could account for channel activation by PIP(2).


Subject(s)
Ion Channel Gating/physiology , Phosphatidylinositols/physiology , Potassium Channels, Inwardly Rectifying/physiology , Amino Acid Sequence , Animals , Humans , Molecular Sequence Data , Phosphatidylinositol 4,5-Diphosphate/physiology , Potassium Channels, Inwardly Rectifying/classification , Potassium Channels, Inwardly Rectifying/genetics
20.
Mol Cell ; 10(3): 469-81, 2002 Sep.
Article in English | MEDLINE | ID: mdl-12408817

ABSTRACT

The molecular mechanism of ion channel gating remains unclear. Using approaches such as proline scanning mutagenesis and homology modeling, we localize the gate of the K(+) channels controlled by the (beta)gamma subunits of G proteins at the pore-lining bundle crossing of the second transmembrane (TM2) helices. We show that the flexibility afforded by a highly conserved glycine residue in the middle of TM2 is crucial for channel gating. In contrast, flexibility introduced immediately below the gate disrupts gating. We propose that the force produced by channel-G(beta)gamma interactions is transduced through the rigid region below the helix bundle crossing to bend TM2 at the glycine that serves as a hinge and open the gate.


Subject(s)
Heterotrimeric GTP-Binding Proteins/metabolism , Ion Channel Gating/physiology , Mutagenesis , Potassium Channels, Inwardly Rectifying , Potassium Channels/metabolism , Protein Structure, Tertiary , Amino Acid Sequence , Animals , G Protein-Coupled Inwardly-Rectifying Potassium Channels , Genes, Reporter , Glycine/metabolism , Heterotrimeric GTP-Binding Proteins/chemistry , Humans , Models, Molecular , Molecular Sequence Data , Oocytes/cytology , Oocytes/physiology , Potassium Channels/chemistry , Potassium Channels/genetics , Proline/metabolism , Protein Structure, Secondary , Protein Subunits/metabolism , Recombinant Fusion Proteins/genetics , Recombinant Fusion Proteins/metabolism , Sequence Alignment , Xenopus laevis
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