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Dive into the research topics where Torsten K. Roepke is active.

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Featured researches published by Torsten K. Roepke.


Nature | 2008

Human cardiovascular progenitor cells develop from a KDR+ embryonic-stem-cell-derived population.

Lei Yang; Mark H. Soonpaa; Eric D. Adler; Torsten K. Roepke; Steven Kattman; Marion Kennedy; Els Henckaerts; Kristina Bonham; Geoffrey W. Abbott; R. Michael Linden; Loren J. Field; Gordon Keller

The functional heart is comprised of distinct mesoderm-derived lineages including cardiomyocytes, endothelial cells and vascular smooth muscle cells. Studies in the mouse embryo and the mouse embryonic stem cell differentiation model have provided evidence indicating that these three lineages develop from a common Flk-1+ (kinase insert domain protein receptor, also known as Kdr) cardiovascular progenitor that represents one of the earliest stages in mesoderm specification to the cardiovascular lineages. To determine whether a comparable progenitor is present during human cardiogenesis, we analysed the development of the cardiovascular lineages in human embryonic stem cell differentiation cultures. Here we show that after induction with combinations of activin A, bone morphogenetic protein 4 (BMP4), basic fibroblast growth factor (bFGF, also known as FGF2), vascular endothelial growth factor (VEGF, also known as VEGFA) and dickkopf homolog 1 (DKK1) in serum-free media, human embryonic-stem-cell-derived embryoid bodies generate a KDRlow/C-KIT(CD117)neg population that displays cardiac, endothelial and vascular smooth muscle potential in vitro and, after transplantation, in vivo. When plated in monolayer cultures, these KDRlow/C-KITneg cells differentiate to generate populations consisting of greater than 50% contracting cardiomyocytes. Populations derived from the KDRlow/C-KITneg fraction give rise to colonies that contain all three lineages when plated in methylcellulose cultures. Results from limiting dilution studies and cell-mixing experiments support the interpretation that these colonies are clones, indicating that they develop from a cardiovascular colony-forming cell. Together, these findings identify a human cardiovascular progenitor that defines one of the earliest stages of human cardiac development.


Journal of Biological Chemistry | 2006

The KCNE2 Potassium Channel Ancillary Subunit Is Essential for Gastric Acid Secretion

Torsten K. Roepke; Arun Anantharam; Philipp Kirchhoff; Stephanie M. Busque; Jeffrey B. Young; John P. Geibel; Daniel J. Lerner; Geoffrey W. Abbott

Genes in the KCNE family encode single transmembrane domain ancillary subunits that co-assemble with voltage-gated potassium (Kv) channel α subunits to alter their function. KCNE2 (also known as MiRP1) is expressed in the heart, is associated with human cardiac arrhythmia, and modulates cardiac Kv α subunits hERG and KCNQ1 in vitro. KCNE2 and KCNQ1 are also expressed in parietal cells, leading to speculation they form a native channel complex there. Here, we disrupted the murine kcne2 gene and found that kcne2 (-/-) mice have a severe gastric phenotype with profoundly reduced parietal cell proton secretion, abnormal parietal cell morphology, achlorhydria, hypergastrinemia, and striking gastric glandular hyperplasia arising from an increase in the number of non-acid secretory cells. KCNQ1 exhibited abnormal distribution in gastric glands from kcne2 (-/-) mice, with increased expression in non-acid secretory cells. Parietal cells from kcne2 (+/-) mice exhibited normal architecture but reduced proton secretion, and kcne2 (+/-) mice were hypochlorhydric, indicating a gene-dose effect and a primary defect in gastric acid secretion. These data demonstrate that KCNE2 is essential for gastric acid secretion, the first genetic evidence that a member of the KCNE gene family is required for normal gastrointestinal function.


Nature Medicine | 2009

Kcne2 deletion uncovers its crucial role in thyroid hormone biosynthesis

Torsten K. Roepke; Elizabeth C. King; Andrea Reyna-Neyra; Monika Paroder; Kerry Purtell; Wade Koba; Eugene J. Fine; Daniel J. Lerner; Nancy Carrasco; Geoffrey W. Abbott

Thyroid dysfunction is a global health concern, causing defects including neurodevelopmental disorders, dwarfism and cardiac arrhythmia. Here, we show that the potassium channel subunits KCNQ1 and KCNE2 form a thyroid-stimulating hormone–stimulated, constitutively active, thyrocyte K+ channel required for normal thyroid hormone biosynthesis. Targeted disruption of Kcne2 in mice impaired thyroid iodide accumulation up to eightfold, impaired maternal milk ejection, halved milk tetraiodothyronine (T4) content and halved litter size. Kcne2-deficient mice had hypothyroidism, dwarfism, alopecia, goiter and cardiac abnormalities including hypertrophy, fibrosis, and reduced fractional shortening. The alopecia, dwarfism and cardiac abnormalities were alleviated by triiodothyronine (T3) and T4 administration to pups, by supplementing dams with T4 before and after they gave birth or by feeding the pups exclusively from Kcne2+/+ dams; conversely, these symptoms were elicited in Kcne2+/+ pups by feeding exclusively from Kcne2−/− dams. These data provide a new potential therapeutic target for thyroid disorders and raise the possibility of an endocrine component to previously identified KCNE2- and KCNQ1-linked human cardiac arrhythmias.


The FASEB Journal | 2008

Targeted deletion of kcne2 impairs ventricular repolarization via disruption of IK,slow1 and Ito,f

Torsten K. Roepke; Andrianos Kontogeorgis; Christopher Ovanez; Xianghua Xu; Jeffrey B. Young; Kerry Purtell; Peter A. Goldstein; David J. Christini; Nicholas S. Peters; Fadi G. Akar; David E. Gutstein; Daniel J. Lerner; Geoffrey W. Abbott

Mutations in human KCNE2, which encodes the MiRP1 potassium channel ancillary subunit, associate with long QT syndrome (LQTS), a defect in ventricular repolarization. The precise cardiac role of MiRP1 remains controversial, in part, because it has marked functional promiscuity in vitro. Here, we disrupted the murine kcne2 gene to define the role of MiRP1 in murine ventricles. kcne2 disruption prolonged ventricular action potential duration (APD), suggestive of reduced repolarization capacity. Accordingly, kcne2 (−/−) ventricles exhibited a 50% reduction in IK,slow1, generated by Kv1.5—a previously unknown partner for MiRP1. Ito,f, generated by Kv4 α subunits, was also diminished, by ~25%. Ventricular MiRP1 protein coimmunoprecipitated with native Kv1.5 and Kv4.2 but not Kv1.4 or Kv4.3. Unexpectedly, kcne2 (−/−) ventricular membrane fractions exhibited 50% less mature Kv1.5 protein than wild type, and disruption of Kv1.5 trafficking to the intercalated discs. Consistent with the reduction in ventricular K+ currents and prolonged ventricular APD, kcne2 deletion lengthened the QTc under sevoflurane anesthesia. Thus, targeted disruption of kcne2 has revealed a novel cardiac partner for MiRP1, a novel role for MiRPs in α subunit targeting in vivo, and a role for MiRP1 in murine ventricular repolarization with parallels to that proposed for the human heart.—Roepke, T. K., Kontogeorgis, A., Ovanez, C., Xu, X., Young, J. B., Purtell, K., Goldstein, P. A., Christini, D. J., Peters, N. S., Akar, F. G., Gutstein, D. E., Lerner, D. J., Abbott, G. W. Targeted deletion of kcne2 impairs ventricular repolarization via disruption of IK,slow1 and Ito,f. FASEB J. 22, 3648–3660 (2008)


PLOS ONE | 2010

Targeted Deletion of Kcne2 Causes Gastritis Cystica Profunda and Gastric Neoplasia

Torsten K. Roepke; Kerry Purtell; Elizabeth C. King; Krista La Perle; Daniel J. Lerner; Geoffrey W. Abbott

Gastric cancer is the second leading cause of cancer death worldwide. Predisposing factors include achlorhydria, Helicobacter pylori infection, oxyntic atrophy and TFF2-expressing metaplasia. In parietal cells, apical potassium channels comprising the KCNQ1 α subunit and the KCNE2 β subunit provide a K+ efflux current to facilitate gastric acid secretion by the apical H+K+ATPase. Accordingly, genetic deletion of murine Kcnq1 or Kcne2 impairs gastric acid secretion. Other evidence has suggested a role for KCNE2 in human gastric cancer cell proliferation, independent of its role in gastric acidification. Here, we demonstrate that 1-year-old Kcne2 −/− mice in a pathogen-free environment all exhibit a severe gastric preneoplastic phenotype comprising gastritis cystica profunda, 6-fold increased stomach mass, increased Ki67 and nuclear Cyclin D1 expression, and TFF2- and cytokeratin 7-expressing metaplasia. Some Kcne2 −/−mice also exhibited pyloric polypoid adenomas extending into the duodenum, and neoplastic invasion of thin walled vessels in the sub-mucosa. Finally, analysis of human gastric cancer tissue indicated reduced parietal cell KCNE2 expression. Together with previous findings, the results suggest KCNE2 disruption as a possible risk factor for gastric neoplasia.


Science Signaling | 2014

KCNQ1, KCNE2, and Na(+)-coupled solute transporters form reciprocally regulating complexes that affect neuronal excitability

Geoffrey W. Abbott; Kwok-Keung Tai; Daniel L. Neverisky; Alex Hansler; Zhaoyang Hu; Torsten K. Roepke; Daniel J. Lerner; Qiuying Chen; Li Liu; Bojana Zupan; Miklós Tóth; Robin L. Haynes; Xiaoping Huang; Didem Demirbas; Roberto Buccafusca; Steven S. Gross; Vikram A. Kanda; Gerard T. Berry

Complexes of solute transporters and potassium channels that reciprocally regulate each other may contribute to seizure susceptibility. Stopping Seizures The activity of potassium channels limits neuronal excitability, and mutations in the regulatory subunit (KCNE2), which promotes the activity of the potassium-conducting pore (KCNQ1), are associated with increased seizure susceptibility. Abbott et al. found that SMIT1, which transports the molecule myo-inositol, associated with KCNQ1 or KCNQ1-KCNE2 complexes. When complexed with KCNE2, KCNQ1 is constitutively active. SMIT1 activity was increased in the presence of KCNQ1 but was inhibited in the presence of KCNQ1-KCNE2. SMIT1 increased the activity of both KCNQ1 and KCNQ1-KCNE2 complexes. The increased seizure activity of mice deficient in KCNE2 was attenuated by administration of myo-inositol, suggesting that a decrease in SMIT1 activity or alterations in the activity of these molecular complexes may contribute to seizure susceptibility. Na+-coupled solute transport is crucial for the uptake of nutrients and metabolic precursors, such as myo-inositol, an important osmolyte and precursor for various cell signaling molecules. We found that various solute transporters and potassium channel subunits formed complexes and reciprocally regulated each other in vitro and in vivo. Global metabolite profiling revealed that mice lacking KCNE2, a K+ channel β subunit, showed a reduction in myo-inositol concentration in cerebrospinal fluid (CSF) but not in serum. Increased behavioral responsiveness to stress and seizure susceptibility in Kcne2−/− mice were alleviated by injections of myo-inositol. Suspecting a defect in myo-inositol transport, we found that KCNE2 and KCNQ1, a voltage-gated potassium channel α subunit, colocalized and coimmunoprecipitated with SMIT1, a Na+-coupled myo-inositol transporter, in the choroid plexus epithelium. Heterologous coexpression demonstrated that myo-inositol transport by SMIT1 was augmented by coexpression of KCNQ1 but was inhibited by coexpression of both KCNQ1 and KCNE2, which form a constitutively active, heteromeric K+ channel. SMIT1 and the related transporter SMIT2 were also inhibited by a constitutively active mutant form of KCNQ1. The activities of KCNQ1 and KCNQ1-KCNE2 were augmented by SMIT1 and the glucose transporter SGLT1 but were suppressed by SMIT2. Channel-transporter signaling complexes may be a widespread mechanism to facilitate solute transport and electrochemical crosstalk.


Cardiovascular Research | 2009

MinK-dependent internalization of the IKs potassium channel

Xianghua Xu; Vikram A. Kanda; Eun Choi; Gianina Panaghie; Torsten K. Roepke; Stephen A. Gaeta; David J. Christini; Daniel J. Lerner; Geoffrey W. Abbott

AIMS KCNQ1-MinK potassium channel complexes (4alpha:2beta stoichiometry) generate IKs, the slowly activating human cardiac ventricular repolarization current. The MinK ancillary subunit slows KCNQ1 activation, eliminates its inactivation, and increases its unitary conductance. However, KCNQ1 transcripts outnumber MinK transcripts five to one in human ventricles, suggesting KCNQ1 also forms other heteromeric or even homomeric channels there. Mechanisms governing which channel types prevail have not previously been reported, despite their significance: normal cardiac rhythm requires tight control of IKs density and kinetics, and inherited mutations in KCNQ1 and MinK can cause ventricular fibrillation and sudden death. Here, we describe a novel mechanism for this control. METHODS AND RESULTS Whole-cell patch-clamping, confocal immunofluorescence microscopy, antibody feeding, biotin feeding, fluorescent transferrin feeding, and protein biochemistry techniques were applied to COS-7 cells heterologously expressing KCNQ1 with wild-type or mutant MinK and dynamin 2 and to native IKs channels in guinea-pig myocytes. KCNQ1-MinK complexes, but not homomeric KCNQ1 channels, were found to undergo clathrin- and dynamin 2-dependent internalization (DDI). Three sites on the MinK intracellular C-terminus were, in concert, necessary and sufficient for DDI. Gating kinetics and sensitivity to XE991 indicated that DDI decreased cell-surface KCNQ1-MinK channels relative to homomeric KCNQ1, decreasing whole-cell current but increasing net activation rate; inhibiting DDI did the reverse. CONCLUSION The data redefine MinK as an endocytic chaperone for KCNQ1 and present a dynamic mechanism for controlling net surface Kv channel subunit composition-and thus current density and gating kinetics-that may also apply to other alpha-beta type Kv channel complexes.


The FASEB Journal | 2011

KCNE2 forms potassium channels with KCNA3 and KCNQ1 in the choroid plexus epithelium

Torsten K. Roepke; Vikram A. Kanda; Kerry Purtell; Elizabeth C. King; Daniel J. Lerner; Geoffrey W. Abbott

Cerebrospinal fluid (CSF) is crucial for normal function and mechanical protection of the CNS. The choroid plexus epithelium (CPe) is primarily responsible for secreting CSF and regulating its composition by mechanisms currently not fully understood. Previously, the heteromeric KCNQ1‐KCNE2 K+ channel was functionally linked to epithelial processes including gastric acid secretion and thyroid hormone biosynthesis. Here, using Kcne2–/– tissue as a negative control, we found cerebral expression of KCNE2 to be markedly enriched in the CPe apical membrane, where we also discovered expression of KCNQ1. Targeted Kcne2 gene deletion in C57B6 mice increased CPe outward K+ current 2‐fold. The Kcne2 deletion‐enhanced portion of the current was inhibited by XE991 (10 μM) and margatoxin (10 μM) but not by dendrotoxin (100 nM), indicating that it arose from augmentation of KCNQ subfamily and KCNA3 but not KCNA1 K+ channel activity. Kcne2 deletion in C57B6 mice also altered the polarity of CPe KCNQ1 and KCNA3 trafficking, hyperpolarized the CPe membrane by 9 ± 2 mV, and increased CSF [Cl–] by 14% compared with wild‐type mice. These findings constitute the first report of CPe dysfunction caused by cation channel gene disruption and suggest that KCNE2 influences blood‐CSF anion flux by regulating KCNQ1 and KCNA3 in the CPe.—Roepke, T. K., Kanda, V. A., Purtell, K., King, E. C., Lerner, D. J., Abbott, G. W. KCNE2 forms potassium channels with KCNA3 and KCNQ1 in the choroid plexus epithelium. FASEB J. 25, 4264–4273 (2011). www.fasebj.org


The FASEB Journal | 2011

Genetic dissection reveals unexpected influence of beta subunits on KCNQ1 K+ channel polarized trafficking in vivo

Torsten K. Roepke; Elizabeth C. King; Kerry Purtell; Vikram A. Kanda; Daniel J. Lerner; Geoffrey W. Abbott

Targeted deletion of the Kcne2 potassium channel β subunit gene ablates gastric acid secretion and predisposes to gastric neoplasia in mice. Here, we discovered that Kcne2 deletion basolaterally reroutes the Kcnq1 α subunit in vivo in parietal cells (PCs), in which the normally apical location of the Kcnq1‐Kcne2 channel facilitates its essential role in gastric acid secretion. Quantitative RT‐PCR and Western blotting revealed that Kcne2 deletion remodeled fundic Kcne3 (2.9±0.8‐fold mRNA increase, n=10;5.3± 0.4‐fold protein increase, n=7) but not Kcne1, 4, or 5, and resulted in basolateral Kcnq1‐Kcne3 complex formation in Kcne2−/− PCs. Concomitant targeted deletion of Kcne3 (creating Kcne2−/−Kcne3−/− mice) restored PC apical Kcnq1 localization without Kcnel, 4, or 5 remodeling (assessed by quantitative RT‐PCR;n=5–10), indicating Kcne3 actively, basolaterally rerouted Kcnq1 in Kcne2−/− PCs. Despite this, Kcne3 deletion exacerbated gastric hyperplasia in Kcne2−/− mice, and both hypochlo‐rhydria and hyperplasia in Kcne2+/− mice, suggesting that Kcne3 up‐regulation was beneficial in Kcne2‐depleted PCs. The findings reveal, in vivo, Kcne‐dependent α subunit polarized trafficking and the existence and consequences of potassium channel β subunit remodeling.—Roepke, T. K., King, E. C., Purtell, K., Kanda, V. A., Lerner, D. J., Abbott, G. W. Genetic dissection reveals unexpected influence of β subunits on KCNQ1 K+ channel polarized trafficking in vivo. FASEB J. 25, 727–736 (2011). www.fasebj.org


The International Journal of Biochemistry & Cell Biology | 2010

Cardiac arrhythmia and thyroid dysfunction: a novel genetic link.

Kerry Purtell; Torsten K. Roepke; Geoffrey W. Abbott

Inherited Long QT Syndrome (LQTS), a cardiac arrhythmia that predisposes to the often lethal ventricular fibrillation, is commonly linked to mutations in KCNQ1. The KCNQ1 voltage-gated K(+) channel α subunit passes ventricular myocyte K(+) current that helps bring a timely end to each heart-beat. KCNQ1, like many K(+) channel α subunits, is regulated by KCNE β subunits, inherited mutations in which also associate with LQTS. KCNQ1 and KCNE mutations are also associated with atrial fibrillation. It has long been known that thyroid status strongly influences cardiac function, and that thyroid dysfunction causes abnormal cardiac structure and rhythm. We recently discovered that KCNQ1 and KCNE2 form a thyroid-stimulating hormone-stimulated K(+) channel in the thyroid that is required for normal thyroid hormone biosynthesis. Here, we review this novel genetic link between cardiac and thyroid physiology and pathology, and its potential influence upon future therapeutic strategies in cardiac and thyroid disease.

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