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1.
Snezana Maljevic Christian Lerche Guiscard Seebohm Alexi K. Alekov reas E. Busch Holger Lerche 《The Journal of physiology》2003,548(2):353-360
Coexpression of KCNQ2 and KCNQ3 channels results in a 10-fold increased current amplitude compared to that of KCNQ2 alone, suggesting the formation of heteromultimeric channels. There is no interaction of either channel with KCNQ1. We evaluated the C-terminus as a potential interaction domain by construction of chimeras with interchanged C-termini of KCNQ1, KCNQ2 and KCNQ3 and functional expression in Xenopus oocytes. The chimera of KCNQ1 with a KCNQ2 C-terminus (Q1ctQ2) showed an 8-fold increase in current amplitude, and Q1ctQ3 a 3-fold increase when coexpressed with KCNQ3 and KCNQ2, respectively, indicating that the C-terminus contains an interaction domain. To characterize this interacting region, we studied further chimeras of KCNQ1 containing different parts of the KCNQ3 C-terminus for interaction with KCNQ2. We also evaluated short sequences of the KCNQ2 C-terminus for a dominant-negative effect on Q1ctQ3. According to the results of these experiments, functional interaction of KCNQ2 and KCNQ3 requires a highly conserved region of about 80 amino acids, previously called the A-domain, plus either 40 residues downstream of the A-domain (B-domain) or the proximal C-terminus between S6 and the A-domain. Furthermore, the chimeras Q1ctQ3 and Q2ctQ3 showed > 10-fold increased current amplitudes compared to KCNQ1 or KCNQ2 alone and a strong depolarizing shift of voltage-dependent activation. The proximal part of the KCNQ3 C-terminus was necessary to produce these effects. Our results indicate that specific parts of the C-terminus enable the interaction between KCNQ2 and KCNQ3 channels and that different parts of the KCNQ3 C-terminus are important for regulating current amplitude. 相似文献
2.
Patience Seebohm Sarah Chaudhary Melanie Boyce Ruth Elkan Mark Avis Carol Munn‐Giddings 《Health & social care in the community》2013,21(4):391-401
This article explores the contribution of self‐help/mutual aid groups to mental well‐being. Self‐help/mutual aid groups are self‐organising groups where people come together to address a shared a health or social issue through mutual support. They are associated with a range of health and social benefits, but remain poorly understood. This article draws on data from stage one of ESTEEM, a project which runs from 2010 to 2013. Stage one ran from 2010 to 2011 and involved participatory, qualitative research carried out in two UK sites. Twenty‐one groups were purposively selected to include a range of focal issues, longevity, structures and ethnic backgrounds. Researchers carried out 21 interviews with group coordinators and twenty group discussions with members to explore the groups' purpose, nature and development. Preliminary analysis of the data suggested that mental well‐being was a common theme across the groups. Subsequently the data were re‐analysed to explore the groups' contribution to mental well‐being using a checklist of protective factors for mental well‐being as a coding framework. The findings showed that groups made a strong contribution to members' mental well‐being by enhancing a sense of control, increasing resilience and facilitating participation. Group members were uplifted by exchanging emotional and practical support; they gained self‐esteem, knowledge and confidence, thereby increasing their control over their situation. For some groups, socio‐economic factors limited their scope and threatened their future. The article provides an evidence‐base which illustrates how self‐help/mutual aid groups can enhance mental well‐being. If supported within a strategy for social justice, these groups enable people with varied concerns to develop a tailored response to their specific needs. The authors suggest that policy‐makers engage with local people, investing in support proportionate to the needs of different populations, enabling them to develop their own self‐help/mutual aid groups to enhance their sense of mental well‐being. 相似文献
3.
Seebohm G 《Molecular pharmacology》2005,67(3):585-588
Cation channels are membrane proteins that provide controlled pathways for ion passage through cellular membranes. They play important roles in physiological processes such as secretory transduction, control of ion homeostasis, cell volume, vesicle cycling, and electrical control of excitable tissues. In a variety of channelopathies, ion channel function is reduced, and activators of cation channels are promising candidates to regain channel function in acquired or inherited channelopathies. Shortage in cation channel activators prevents testing of efficiency of activators in a variety of indications. This shortage might result from the relative incapability of modern drug screening methods, but increasing knowledge about cation channel activator binding and action might enable us in the future to use in silico-guided drug design of channel modulators. New compounds such as the HERG channel activator (3R,4R)-4-[3-(6-methoxy-quinolin-4-yl)-3-oxo-propyl]-1-[3-(2,3,5-trifluoro-phenyl)-prop-2-ynyl]-piperidine-3-carboxylic acid (RPR260243) will enable us to increase our understanding in cation channel modulation and to test the concept of channel activation as a clinically relevant principle in treatment of channelopathies. 相似文献
4.
Lerche C Seebohm G Wagner CI Scherer CR Dehmelt L Abitbol I Gerlach U Brendel J Attali B Busch AE 《British journal of pharmacology》2000,131(8):1503-1506
Slowly activating I:(Ks) (KCNQ1/MinK) channels were expressed in Xenopous: oocytes and their sensitivity to chromanols was compared to homomeric KCNQ1 channels. To elucidate the contribution of the ss-subunit MinK on chromanol block, a formerly described chromanol HMR 1556 and its enantiomer S5557 were tested for enantio-specificity in blocking I:(Ks) and KCNQ1 as shown for the single enantiomers of chromanol 293B. Both enantiomers blocked homomeric KCNQ1 channels to a lesser extent than heteromeric I:(Ks) channels. Furthermore, we expressed both WT and mutant MinK subunits to examine the involvement of particular MinK protein regions in channel block by chromanols. Through a broad variety of MinK deletion and point mutants, we could not identify amino acids or regions where sensitivity was abolished or strikingly diminished (>2.5 fold). This could indicate that MinK does not directly take part in chromanol binding but acts allosterically to facilitate drug binding to the principal subunit KCNQ1. 相似文献
5.
Thomas V. Wuttke Johann Penzien Michael Fauler Guiscard Seebohm Frank Lehmann-Horn Holger Lerche Karin Jurkat-Rott 《The Journal of physiology》2008,586(2):545-555
The voltage-gated potassium channels KV 7.2 and KV 7.3 (genes KCNQ2 and KCNQ3 ) constitute a major component of the M-current controlling the firing rate in many neurons. Mutations within these two channel subunits cause benign familial neonatal convulsions (BFNC). Here we identified a novel BFNC-causing mutation (E119G) in the S1–S2 region of KV 7.2. Electrophysiological investigations in Xenopus oocytes using two-microelectrode voltage clamping revealed that the steady-state activation curves for E119G alone and its coexpressions with KV 7.2 and/or KV 7.3 wild-type (WT) channels were significantly shifted in the depolarizing direction compared to KV 7.2 or KV 7.2/KV 7.3. These shifts reduced the relative current amplitudes for mutant channels particularly in the subthreshold range of an action potential (about 45% reduction at −50 mV for E119G compared to KV 7.2, and 33% for E119G/KV 7.3 compared to KV 7.2/KV 7.3 channels). Activation kinetics were significantly slowed for mutant channels. Our results indicate that small changes in channel gating at subthreshold voltages are sufficient to cause neonatal seizures and demonstrate the importance of the M-current for this voltage range. This was confirmed by a computer model predicting an increased burst duration for the mutation. On a molecular level, these results reveal a critical role in voltage sensing of the negatively charged E119 in S1–S2 of KV 7.2, a region that – according to molecular modelling – might interact with a positive charge in the S4 segment. 相似文献
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7.
Morokuma J Blackiston D Adams DS Seebohm G Trimmer B Levin M 《Proceedings of the National Academy of Sciences of the United States of America》2008,105(43):16608-16613
Ion transporters, and the resulting voltage gradients and electric fields, have been implicated in embryonic development and regeneration. These biophysical signals are key physiological aspects of the microenvironment that epigenetically regulate stem and tumor cell behavior. Here, we identify a previously unrecognized function for KCNQ1, a potassium channel known to be involved in human Romano-Ward and Jervell-Lange-Nielsen syndromes when mutated. Misexpression of its modulatory wild-type beta-subunit XKCNE1 in the Xenopus embryo resulted in a striking alteration of the behavior of one type of embryonic stem cell: the pigment cell lineage of the neural crest. Depolarization of embryonic cells by misexpression of KCNE1 non-cell-autonomously induced melanocytes to overproliferate, spread out, and become highly invasive of blood vessels, liver, gut, and neural tube, leading to a deeply hyperpigmented phenotype. This effect is mediated by the up-regulation of Sox10 and Slug genes, thus linking alterations in ion channel function to the control of migration, shape, and mitosis rates during embryonic morphogenesis. Taken together, these data identify a role for the KCNQ1 channel in regulating key cell behaviors and reveal the molecular identity of a biophysical switch, by means of which neoplastic-like properties can be conferred upon a specific embryonic stem cell subpopulation. 相似文献
8.
Fedorenko O Strutz-Seebohm N Henrion U Ureche ON Lang F Seebohm G Lang UE 《Psychopharmacology》2008,199(1):47-54
RATIONALE: Evidence for an association between phosphatidylinositol-4-phosphate 5-kinase II alpha (PIP5K2A) and schizophrenia was recently obtained and replicated in several samples. PIP5K2A controls the function of KCNQ channels via phosphatidylinositol-4,5-bisphosphate (PIP2) synthesis. Interestingly, recent data suggest that KCNQ channels suppress basal activity of dopaminergic neurons and dopaminergic firing. Activation of KCNQ accordingly attenuates the central stimulating effects of dopamine, cocaine, methylphenidate, and phenylcyclidine. OBJECTIVE: The aim of this study was to explore the functional relevance of PIP5K2A, which might influence schizophrenic behavior. MATERIALS AND METHODS: Here, we study the effects of the neuronal PIP5K2A on KCNQ2, KCNQ5, KCNQ2/KCNQ3, and KCNQ3/KCNQ5 in the Xenopus expression system. RESULTS: We find that wild-type PIP5K2A but not the schizophrenia-associated mutant (N251S)-PIP5K2A activates heteromeric KCNQ2/KCNQ3 and KCNQ3/KCNQ5, the molecular correlate of neuronal M channels. Homomeric KCNQ2 and KCNQ5 channels were not activated by the kinase indicating that the presence of KCNQ3 in the channel complex is required for the kinase-mediated effects. Acute application of PI(4,5)P2 and a PIP2 scavenger indicates that the mutation N251S renders the kinase PIP5K2A inactive. CONCLUSIONS: Our results suggest that the schizophrenia-linked mutation of the kinase results in reduced KCNQ channel function and thereby might explain the loss of dopaminergic control in schizophrenic patients. Moreover, the addictive potential of dopaminergic drugs often observed in schizophrenic patients might be explained by this mechanism. At least, the insufficiency of (N251S)-PIP5K2A to stimulate neuronal M channels may contribute to the clinical phenotype of schizophrenia. 相似文献
9.
Strutz-Seebohm N Seebohm G Korniychuk G Baltaev R Ureche O Striegel M Lang F 《Pflügers Archiv : European journal of physiology》2006,452(3):276-282
The serum- and glucocorticoid-inducible kinase isoform 3 (SGK3) and stargazin have both been shown to enhance the synaptic expression level of GluR1. The present study was performed to elucidate whether SGK3 and stargazin interact or are effective through different pathways in the regulation of GluR1. Proteins were expressed in Xenopus oocytes by injection of complementary RNA (cRNA) encoding GluR1, SGK isoforms, and/or stargazin. In oocytes expressing GluR1 6 days after cRNA injection, glutamate induced an inward current (IGlu), which was increased approximately fourfold following coexpression of SGK3. Coexpression of stargazin similarly enhanced IGlu. Coexpression of both SGK3 and stargazin stimulated the current by a factor of 15.5. Replacement of the serine by alanine at the only SGK consensus sequence (RXRXXS/T) in stargazin enhanced the efficacy of stargazin but did not prevent further stimulation of IGlu by additional coexpression of SGK3. Western blotting showed that stargazin accelerated membrane insertion of GluR1 protein leading to enhanced GluR1 plasma membrane protein abundance 2 days, but not 6 days, after cRNA injection, while SGK3 increased plasma membrane protein abundance 6 days after cRNA injection. In conclusion, SGK3 and stargazin regulate GluR1 independently, and thus, their effects on glutamate-induced currents are additive. 相似文献
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