@article{MTMT:32597571, title = {Impact of lipid rafts on transient receptor potential channel activities}, url = {https://m2.mtmt.hu/api/publication/32597571}, author = {Bobkov, D. and Semenova, S.}, doi = {10.1002/jcp.30679}, journal-iso = {J CELL PHYSIOL}, journal = {JOURNAL OF CELLULAR PHYSIOLOGY}, volume = {237}, unique-id = {32597571}, issn = {0021-9541}, year = {2022}, eissn = {1097-4652}, pages = {2034-2044} } @article{MTMT:33344914, title = {The Role of Membrane Lipids in Light-Activation of Drosophila TRP Channels}, url = {https://m2.mtmt.hu/api/publication/33344914}, author = {Gutorov, Rita and Katz, Ben and Rhodes-Mordov, Elisheva and Zaguri, Rachel and Brandwine-Shemmer, Tal and Minke, Baruch}, doi = {10.3390/biom12030382}, journal-iso = {BIOMOLECULES}, journal = {BIOMOLECULES}, volume = {12}, unique-id = {33344914}, issn = {2218-273X}, abstract = {Transient Receptor Potential (TRP) channels constitute a large superfamily of polymodal channel proteins with diverse roles in many physiological and sensory systems that function both as ionotropic and metabotropic receptors. From the early days of TRP channel discovery, membrane lipids were suggested to play a fundamental role in channel activation and regulation. A prominent example is the Drosophila TRP and TRP-like (TRPL) channels, which are predominantly expressed in the visual system of Drosophila. Light activation of the TRP and TRPL channels, the founding members of the TRP channel superfamily, requires activation of phospholipase C beta (PLC), which hydrolyzes phosphatidylinositol 4,5-bisphosphate (PIP2) into Diacylglycerol (DAG) and Inositol 1,4,5-trisphosphate (IP3). However, the events required for channel gating downstream of PLC activation are still under debate and led to several hypotheses regarding the mechanisms by which lipids gate the channels. Despite many efforts, compelling evidence of the involvement of DAG accumulation, PIP2 depletion or IP3-mediated Ca2+ release in light activation of the TRP/TRPL channels are still lacking. Exogeneous application of poly unsaturated fatty acids (PUFAs), a product of DAG hydrolysis was demonstrated as an efficient way to activate the Drosophila TRP/TRPL channels. However, compelling evidence for the involvement of PUFAs in physiological light-activation of the TRP/TRPL channels is still lacking. Light-induced mechanical force generation was measured in photoreceptor cells prior to channel opening. This mechanical force depends on PLC activity, suggesting that the enzymatic activity of PLC converting PIP2 into DAG generates membrane tension, leading to mechanical gating of the channels. In this review, we will present the roles of membrane lipids in light activation of Drosophila TRP channels and present the many advantages of this model system in the exploration of TRP channel activation under physiological conditions.}, keywords = {cholesterol; ergosterol; methyl-beta-cyclodextrin; phospholipase C beta; Diacylglycerol (DAG); TRPL channel; Diacylglycerol kinase (DGK); Drosophila TRP channel; poly unsaturated fatty acids (PUFAs)}, year = {2022}, eissn = {2218-273X} } @article{MTMT:31851708, title = {Origins of eukaryotic excitability}, url = {https://m2.mtmt.hu/api/publication/31851708}, author = {Wan, Kirsty Y. and Jékely, Gáspár}, doi = {10.1098/rstb.2019.0758}, journal-iso = {PHILOS T ROY SOC B}, journal = {PHILOSOPHICAL TRANSACTIONS OF THE ROYAL SOCIETY B - BIOLOGICAL SCIENCES}, volume = {376}, unique-id = {31851708}, issn = {0962-8436}, year = {2021}, eissn = {1471-2970}, orcid-numbers = {Wan, Kirsty Y./0000-0002-0291-328X; Jékely, Gáspár/0000-0001-8496-9836} } @article{MTMT:31505504, title = {The fat brain}, url = {https://m2.mtmt.hu/api/publication/31505504}, author = {Montesinos, Jorge and Guardia-Laguarta, Cristina and Area-Gomez, Estela}, doi = {10.1097/MCO.0000000000000634}, journal-iso = {CURR OPIN CLIN NUTR}, journal = {CURRENT OPINION IN CLINICAL NUTRITION AND METABOLIC CARE}, volume = {23}, unique-id = {31505504}, issn = {1363-1950}, abstract = {Purpose of review The purpose of this brief review is to gain an understanding on the multiple roles that lipids exert on the brain, and to highlight new ideas in the impact of lipid homeostasis in the regulation of synaptic transmission. Recent findings Recent data underline the crucial function of lipid homeostasis in maintaining neuronal function and synaptic plasticity. Moreover, new advances in analytical approaches to study lipid classes and species is opening a new door to understand and monitor how alterations in lipid pathways could shed new light into the pathogenesis of neurodegeneration. Lipids are one of the most essential elements of the brain. However, our understanding of the role of lipids within the central nervous system is still largely unknown. Identifying the molecular mechanism (s) by which lipids can regulate neuronal transmission represents the next frontier in neuroscience, and a new challenge in our understanding of the brain and the mechanism(s) behind neurological disorders.}, keywords = {cholesterol; lipid raft; LIPIDOMICS; Gangliosides}, year = {2020}, eissn = {1473-6519}, pages = {68-75} } @article{MTMT:31312818, title = {Direct and indirect cholesterol effects on membrane proteins with special focus on potassium channels}, url = {https://m2.mtmt.hu/api/publication/31312818}, author = {Zákány, Florina and Kovács, Tamás and Panyi, György and Varga, Zoltán}, doi = {10.1016/j.bbalip.2020.158706}, journal-iso = {BBA-MOL CELL BIOL L}, journal = {BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR AND CELL BIOLOGY OF LIPIDS}, volume = {1865}, unique-id = {31312818}, issn = {1388-1981}, abstract = {As described in the literature the interaction between cholesterol and membrane proteins can occur via direct, ligand-like and indirect mechanisms, in which cholesterol effects are mediated by alterations in the biophysical properties or in the protein-organizing functions of the lipid membrane. Early studies emphasized the importance of indirect and raft-mediated effects, but improvements in computational and structural imaging techniques allowed the definition of a wide range of functionally active cholesterol binding domains and sites suggesting the relevance of direct cholesterol effects in various proteins. However, the intramolecular rearrangements induced by cholesterol leading to modulation of ion channel gating, membrane transport and receptor functions still have not been revealed. In this review we summarize the novel findings of the topic by focusing on recent studies about direct and indirect effects of cholesterol on potassium ion channels, and we extend the review to transporters and receptors with different domain structures to introduce the general mechanisms of cholesterol action among membrane proteins. We propose that rather than pure direct or indirect effects, cholesterol action on membrane proteins can be better described as a mixture of indirect and direct interactions with system-specific variability in their contributions, which can be explored by using a multi-level approach employing multiple experimental techniques. © 2020 The Authors}, keywords = {calcium; RECEPTORS; SODIUM; POTASSIUM; ION CHANNELS; TRANSPORTERS; review; membrane protein; priority journal; biosynthesis; transient receptor potential channel; HYDRATION; PROTEIN FUNCTION; elasticity; cholesterol; cholesterol; ion channel; adenosine triphosphatase (potassium sodium); binding affinity; chemical structure; epidermal growth factor receptor; protein domain; potassium channel; calcium channel; Hydrophobicity; structure analysis; electric potential; dipole; ABC transporter; protein interaction; lipid raft; G protein coupled receptor; protein tyrosine kinase; Membrane transport; protein motif; voltage gated potassium channel; membrane potential; channel gating; chemical stress; potassium conductance; Hedgehog signaling; ligand gated ion channel; Direct cholesterol effects; Indirect cholesterol effects}, year = {2020}, eissn = {1879-2618}, orcid-numbers = {Kovács, Tamás/0000-0002-1084-9847; Panyi, György/0000-0001-6227-3301} } @article{MTMT:30663422, title = {Parabolic, Flight-Induced, Acute Hypergravity and Microgravity Effects on the Beating Rate of Human Cardiomyocytes}, url = {https://m2.mtmt.hu/api/publication/30663422}, author = {Acharya, Aviseka and Brungs, Sonja and Lichterfeld, Yannick and Hescheler, Jürgen and Hemmersbach, Ruth and Boeuf, Helene and Sachinidis, Agapios}, doi = {10.3390/cells8040352}, journal-iso = {CELLS-BASEL}, journal = {CELLS}, volume = {8}, unique-id = {30663422}, year = {2019}, eissn = {2073-4409} } @{MTMT:31069060, title = {Chiral Specificity of Cholesterol Orientation Within Cholesterol Binding Sites in Inwardly Rectifying K+ Channels}, url = {https://m2.mtmt.hu/api/publication/31069060}, author = {Barbera, Nicolas and Levitan, Irena}, booktitle = {Direct Mechanisms in Cholesterol Modulation of Protein Function}, doi = {10.1007/978-3-030-04278-3_4}, unique-id = {31069060}, abstract = {Cholesterol is an integral component of cellular membranes and has been shown to be an important functional regulator for many different ion channels, including inwardly rectifying potassium (Kir) channels. Consequently, understanding the molecular mechanisms underlying this regulation represents a critical field of study. Broadly speaking, cholesterol can mediate ion channel function either directly by binding to specific sites or indirectly by altering surrounding membrane properties. Owing to the similar effects of cholesterol and its chiral isomers (epicholesterol and ent-cholesterol) on membrane properties, comparative analysis of these sterols can be an effective tool for discriminating between these direct and indirect effects. Indeed, this strategy was used to demonstrate the direct effect of cholesterol on Kir channel function. However, while this approach can discriminate between direct and indirect effects, it does not account for the promiscuity of cholesterol binding sites, which can potentially accommodate cholesterol or its chiral isomers. In this chapter, we use docking analyses to explore the idea that the specificity of cholesterol's effect on Kir channels is dependent on the specific orientation of cholesterol within its putative binding pocket which its chiral isomers cannot replicate, even when bound themselves.}, keywords = {Kir channels; Cholesterol binding; Cholesterol stereoisomers}, year = {2019}, pages = {77-95} } @article{MTMT:31041858, title = {Modulation of transient receptor potential c channel activity by cholesterol}, url = {https://m2.mtmt.hu/api/publication/31041858}, author = {Gutorov, R. and Peters, M. and Katz, B. and Brandwine, T. and Barbera, N.A. and Levitan, I. and Minke, B.}, doi = {10.3389/fphar.2019.01487}, journal-iso = {FRONT PHARMACOL}, journal = {FRONTIERS IN PHARMACOLOGY}, volume = {10}, unique-id = {31041858}, abstract = {Changes of cholesterol level in the plasma membrane of cells have been shown to modulate ion channel function. The proposed mechanisms underlying these modulations include association of cholesterol to a single binding site at a single channel conformation, association to a highly flexible cholesterol binding site adopting multiple poses, and perturbation of lipid rafts. These perturbations have been shown to induce reversible targeting of mammalian transient receptor potential C (TRPC) channels to the cholesterol-rich membrane environment of lipid rafts. Thus, the observed inhibition of TRPC channels by methyl-β-cyclodextrin (MβCD), which induces cholesterol efflux from the plasma membrane, may result from disruption of lipid rafts. This perturbation was also shown to disrupt multimolecular signaling complexes containing TRPC channels. The Drosophila TRP and TRP-like (TRPL) channels belong to the TRPC channel subfamily. When the Drosophila TRPL channel was expressed in S2 or HEK293 cells and perfused with MβCD, the TRPL current was abolished in less than 100 s, fitting well the fast kinetic phase of cholesterol sequestration experiments in cells. It was thus suggested that the fast kinetics of TRPL channel suppression by MβCD arise from disruption of lipid rafts. Accordingly, lipid raft perturbation by cholesterol sequestration could give clues to the function of lipid environment in TRPC channel activity and its mechanism. Copyright © 2019 Gutorov, Peters, Katz, Brandwine, Barbera, Levitan and Minke.}, keywords = {LIPID RAFTS; CAVEOLAE; Methyl-β-cyclodextrin; Cholesterol recognition amino acid consensus sequence (CRAC); TRP-like (TRPL) channel}, year = {2019}, eissn = {1663-9812} } @{MTMT:30766400, title = {Cholesterol Binding Sites in Inwardly Rectifying Potassium Channels}, url = {https://m2.mtmt.hu/api/publication/30766400}, author = {Rosenhouse-Dantsker, Avia}, booktitle = {Direct Mechanisms in Cholesterol Modulation of Protein Function}, doi = {10.1007/978-3-030-14265-0_7}, unique-id = {30766400}, abstract = {Inwardly rectifying potassium (Kir) channels play a variety of critical cellular roles including modulating membrane excitability in neurons, cardiomyocytes and muscle cells, and setting the resting membrane potential, heart rate, vascular tone, insulin release, and salt flow across epithelia. These processes are regulated by a variegated list of modulators. In particular, in recent years, cholesterol has been shown to modulate a growing number of Kir channels. Subsequent to the discovery that members of the Kir2 subfamily were down-regulated by cholesterol, we have shown that members of several other Kir subfamilies were also modulated by cholesterol. However, not all cholesterol sensitive Kir channels were down-regulated by cholesterol. Our recent studies focused on three Kir channels: Kir2.1 (IRK1), Kir3.2(boolean AND) (GIRK2(boolean AND)) and Kir3.4* (GIRK4*). Among these, Kir2.1 was down-regulated by cholesterol whereas Kir3.2(boolean AND) and Kir3.4* were both up-regulated by cholesterol. Despite the opposite impact of cholesterol on these Kir3 channels compared to Kir2.1, putative cholesterol binding sites in all three channels were identified in equivalent transmembrane domains. Interestingly, however, there are intriguing differences in the specific residues that interact with the cholesterol molecule in these Kir channels. Here we compare and contrast the molecular characteristics of the putative cholesterol binding sites in the three channels, and discuss the potential implications of the differences for the impact of cholesterol on ion channels.}, keywords = {ION CHANNELS; cholesterol; Protein-lipid interaction; GIRK channels; Kir channels; Channel modulation}, year = {2019}, pages = {119-138} } @article{MTMT:30378432, title = {Determining the target of membrane sterols on voltage-gated potassium channels}, url = {https://m2.mtmt.hu/api/publication/30378432}, author = {Zákány, Florina and Pap, Pál and Papp, Ferenc and Kovács, Tamás and Nagy, Péter and Péter, Mária and Szente, Lajos and Panyi, György and Varga, Zoltán}, doi = {10.1016/j.bbalip.2018.12.006}, journal-iso = {BBA-MOL CELL BIOL L}, journal = {BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR AND CELL BIOLOGY OF LIPIDS}, volume = {1864}, unique-id = {30378432}, issn = {1388-1981}, year = {2019}, eissn = {1879-2618}, pages = {312-325}, orcid-numbers = {Kovács, Tamás/0000-0002-1084-9847; Nagy, Péter/0000-0002-7466-805X; Panyi, György/0000-0001-6227-3301} } @article{MTMT:30572352, title = {Molecular Dynamics Simulations of Kir2.2 Interactions with an Ensemble of Cholesterol Molecules}, url = {https://m2.mtmt.hu/api/publication/30572352}, author = {Barbera, Nicolas and Ayee, Manuela A. A. and Akpa, Belinda S. and Levitan, Irena}, doi = {10.1016/j.bpj.2018.07.041}, journal-iso = {BIOPHYS J}, journal = {BIOPHYSICAL JOURNAL}, volume = {115}, unique-id = {30572352}, issn = {0006-3495}, abstract = {Cholesterol is a major regulator of multiple types of ion channels, but the specific mechanisms and the dynamics of its interactions with the channels are not well understood. Kir2 channels were shown to be sensitive to cholesterol through direct interactions with "cholesterol-sensitive" regions on the channel protein. In this work, we used Martini coarse-grained simulations to analyze the long (us) timescale dynamics of cholesterol with Kir2.2 channels embedded into a model membrane containing POPC phospholipid with 30 mol% cholesterol. This approach allows us to simulate the dynamic, unbiased migration of cholesterol molecules from the lipid membrane environment to the protein surface of Kir2.2 and explore the favorability of cholesterol interactions at both surface sites and recessed pockets of the channel. We found that the cholesterol environment surrounding Kir channels forms a complex milieu of different short- and long-term interactions, with multiple cholesterol molecules concurrently interacting with the channel. Furthermore, utilizing principles from network theory, we identified four discrete cholesterol-binding sites within the previously identified cholesterol-sensitive region that exist depending on the conformational state of the channel-open or closed. We also discovered that a twofold decrease in the cholesterol level of the membrane, which we found earlier to increase Kir2 activity, results in a site-specific decrease of cholesterol occupancy at these sites in both the open and closed states: cholesterol molecules at the deepest of these discrete sites shows no change in occupancy at different cholesterol levels, whereas the remaining sites showed a marked decrease in occupancy.}, year = {2018}, eissn = {1542-0086}, pages = {1264-1280} }