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https://www.readbyqxmd.com/read/29305262/point-mutation-of-a-conserved-aspartate-d69-in-the-muscarinic-m2-receptor-does-not-modify-voltage-sensitive-agonist-potency
#1
Richard Ågren, Kristoffer Sahlholm, Johanna Nilsson, Peter Århem
The muscarinic M2 receptor (M2R) has been shown to display voltage-sensitive agonist binding, based on G protein-activated inward rectifier potassium channel (GIRK) opening and radioligand binding at different membrane voltages. A conserved aspartate in transmembrane segment (TM) II of M2R, D69, has been proposed as the voltage sensor. While a recent paper instead presented evidence of tyrosines in TMs III, VI, and VII acting as voltage sensors, these authors were not able to record GIRK channel activation by a D69N mutant M2R...
January 2, 2018: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/29180115/deletion-of-girk2-subunit-containing-girk-channels-of-neurons-expressing-dopamine-transporter-decrease-immobility-time-on-forced-swimming-in-mice
#2
Ikutaro Honda, Kimi Araki, Sokichi Honda, Fumio Soeda, Min-Chul Shin, Shogo Misumi, Ken-Ichi Yamamura, Kazuo Takahama
We previously reported that non-narcotic antitussives possessing inhibitory actions on G protein-coupled inwardly rectifying potassium (GIRK) channels have antidepressant-like effects in the forced swimming test in normal and adrenocoticotropic hormone (ACTH) treated rats. Furthermore, the antidepressant-like effects of the antitussives such as tipepidine were blocked by dopamine D1 receptor antagonist, and inhibitory actions on GIRK channels of dopamine neurons may be involved in the antidepressant-like effects of tipepidine...
November 24, 2017: Neuroscience Letters
https://www.readbyqxmd.com/read/29177691/differential-association-of-gabab-receptors-with-their-effector-ion-channels-in-purkinje-cells
#3
Rafael Luján, Carolina Aguado, Francisco Ciruela, Javier Cózar, David Kleindienst, Luis de la Ossa, Bernhard Bettler, Kevin Wickman, Masahiko Watanabe, Ryuichi Shigemoto, Yugo Fukazawa
Metabotropic GABAB receptors mediate slow inhibitory effects presynaptically and postsynaptically through the modulation of different effector signalling pathways. Here, we analysed the distribution of GABAB receptors using highly sensitive SDS-digested freeze-fracture replica labelling in mouse cerebellar Purkinje cells. Immunoreactivity for GABAB1 was observed on presynaptic and, more abundantly, on postsynaptic compartments, showing both scattered and clustered distribution patterns. Quantitative analysis of immunoparticles revealed a somato-dendritic gradient, with the density of immunoparticles increasing 26-fold from somata to dendritic spines...
November 25, 2017: Brain Structure & Function
https://www.readbyqxmd.com/read/29131436/gabab-receptors-in-neocortical-and-hippocampal-pyramidal-neurons-are-coupled-to-different-potassium-channels
#4
Jean-Didier Breton, Greg J Stuart
Classically, GABAB receptors are thought to regulate neuronal excitability via G-protein coupled inwardly rectifying potassium (GIRK) channels. Recent data, however, indicates that GABAB receptors can also activate two-pore domain potassium channels. Here, we investigate which potassium channels are coupled to GABAB receptors in rat neocortical layer 5 and hippocampal CA1 pyramidal neurons. Bath application of the non-specific GIRK channel blocker barium (200 μM) abolished outward currents evoked by GABAB receptors in CA1 pyramidal, but only partially blocked GABAB responses in layer 5 neurons...
November 13, 2017: European Journal of Neuroscience
https://www.readbyqxmd.com/read/29126768/increased-functional-coupling-of-5-ht1a-autoreceptors-to-girk-channels-in-tph2-mice
#5
Boris Mlinar, Alberto Montalbano, Jonas Waider, Klaus-Peter Lesch, Renato Corradetti
Firing activity of serotonergic neurons is under regulatory control by somatodendritic 5-HT1A autoreceptors (5-HT1AARs). Enhanced 5-HT1AAR functioning may cause decreased serotonergic signaling in brain and has thereby been implicated in the etiology of mood and anxiety disorders. Tryptophan hydroxylase-2 knockout (Tph2(-/-)) mice exhibit sensitization of 5-HT1A agonist-induced inhibition of serotonergic neuron firing and thus represents a unique animal model of enhanced 5-HT1AAR functioning. To elucidate the mechanisms underlying 5-HT1AAR supersensitivity in Tph2(-/-) mice, we characterized the activation of G protein-coupled inwardly-rectifying potassium (GIRK) conductance by the 5-HT1A receptor agonist 5-carboxamidotryptamine using whole-cell recordings from serotonergic neurons in dorsal raphe nucleus...
November 7, 2017: European Neuropsychopharmacology: the Journal of the European College of Neuropsychopharmacology
https://www.readbyqxmd.com/read/29116174/activation-of-g-protein-gated-inwardly-rectifying-potassium-kir3-girk-channels-rescues-hippocampal-functions-in-a-mouse-model-of-early-amyloid-%C3%AE-pathology
#6
Irene Sánchez-Rodríguez, Sara Temprano-Carazo, Alberto Nájera, Souhail Djebari, Javier Yajeya, Agnès Gruart, José M Delgado-García, Lydia Jiménez-Díaz, Juan D Navarro-López
The hippocampus plays a critical role in learning and memory. Its correct performance relies on excitatory/inhibitory synaptic transmission balance. In early stages of Alzheimer's disease (AD), neuronal hyperexcitability leads to network dysfunction observed in cortical regions such as the hippocampus. G-protein-gated potassium (GirK) channels induce neurons to hyperpolarize, contribute to the resting membrane potential and could compensate any excesses of excitation. Here, we have studied the relationship between GirK channels and hippocampal function in a mouse model of early AD pathology...
November 7, 2017: Scientific Reports
https://www.readbyqxmd.com/read/29116125/erratum-large-meta-analysis-of-genome-wide-association-studies-identifies-five-loci-for-lean-body-mass
#7
M Carola Zillikens, Serkalem Demissie, Yi-Hsiang Hsu, Laura M Yerges-Armstrong, Wen-Chi Chou, Lisette Stolk, Gregory Livshits, Linda Broer, Toby Johnson, Daniel L Koller, Zoltán Kutalik, Jian'an Luan, Ida Malkin, Janina S Ried, Albert V Smith, Gudmar Thorleifsson, Liesbeth Vandenput, Jing Hua Zhao, Weihua Zhang, Ali Aghdassi, Kristina Åkesson, Najaf Amin, Leslie J Baier, Inês Barroso, David A Bennett, Lars Bertram, Rainer Biffar, Murielle Bochud, Michael Boehnke, Ingrid B Borecki, Aron S Buchman, Liisa Byberg, Harry Campbell, Natalia Campos Obanda, Jane A Cauley, Peggy M Cawthon, Henna Cederberg, Zhao Chen, Nam H Cho, Hyung Jin Choi, Melina Claussnitzer, Francis Collins, Steven R Cummings, Philip L De Jager, Ilja Demuth, Rosalie A M Dhonukshe-Rutten, Luda Diatchenko, Gudny Eiriksdottir, Anke W Enneman, Mike Erdos, Johan G Eriksson, Joel Eriksson, Karol Estrada, Daniel S Evans, Mary F Feitosa, Mao Fu, Melissa Garcia, Christian Gieger, Thomas Girke, Nicole L Glazer, Harald Grallert, Jagvir Grewal, Bok-Ghee Han, Robert L Hanson, Caroline Hayward, Albert Hofman, Eric P Hoffman, Georg Homuth, Wen-Chi Hsueh, Monica J Hubal, Alan Hubbard, Kim M Huffman, Lise B Husted, Thomas Illig, Erik Ingelsson, Till Ittermann, John-Olov Jansson, Joanne M Jordan, Antti Jula, Magnus Karlsson, Kay-Tee Khaw, Tuomas O Kilpeläinen, Norman Klopp, Jacqueline S L Kloth, Heikki A Koistinen, William E Kraus, Stephen Kritchevsky, Teemu Kuulasmaa, Johanna Kuusisto, Markku Laakso, Jari Lahti, Thomas Lang, Bente L Langdahl, Lenore J Launer, Jong-Young Lee, Markus M Lerch, Joshua R Lewis, Lars Lind, Cecilia Lindgren, Yongmei Liu, Tian Liu, Youfang Liu, Östen Ljunggren, Mattias Lorentzon, Robert N Luben, William Maixner, Fiona E McGuigan, Carolina Medina-Gomez, Thomas Meitinger, Håkan Melhus, Dan Mellström, Simon Melov, Karl Michaëlsson, Braxton D Mitchell, Andrew P Morris, Leif Mosekilde, Anne Newman, Carrie M Nielson, Jeffrey R O'Connell, Ben A Oostra, Eric S Orwoll, Aarno Palotie, Stephen C J Parker, Munro Peacock, Markus Perola, Annette Peters, Ozren Polasek, Richard L Prince, Katri Räikkönen, Stuart H Ralston, Samuli Ripatti, John A Robbins, Jerome I Rotter, Igor Rudan, Veikko Salomaa, Suzanne Satterfield, Eric E Schadt, Sabine Schipf, Laura Scott, Joban Sehmi, Jian Shen, Chan Soo Shin, Gunnar Sigurdsson, Shad Smith, Nicole Soranzo, Alena Stančáková, Elisabeth Steinhagen-Thiessen, Elizabeth A Streeten, Unnur Styrkarsdottir, Karin M A Swart, Sian-Tsung Tan, Mark A Tarnopolsky, Patricia Thompson, Cynthia A Thomson, Unnur Thorsteinsdottir, Emmi Tikkanen, Gregory J Tranah, Jaakko Tuomilehto, Natasja M van Schoor, Arjun Verma, Peter Vollenweider, Henry Völzke, Jean Wactawski-Wende, Mark Walker, Michael N Weedon, Ryan Welch, H-Erich Wichmann, Elisabeth Widen, Frances M K Williams, James F Wilson, Nicole C Wright, Weijia Xie, Lei Yu, Yanhua Zhou, John C Chambers, Angela Döring, Cornelia M van Duijn, Michael J Econs, Vilmundur Gudnason, Jaspal S Kooner, Bruce M Psaty, Timothy D Spector, Kari Stefansson, Fernando Rivadeneira, André G Uitterlinden, Nicholas J Wareham, Vicky Ossowski, Dawn Waterworth, Ruth J F Loos, David Karasik, Tamara B Harris, Claes Ohlsson, Douglas P Kiel
A correction to this article has been published and is linked from the HTML version of this article.
November 7, 2017: Nature Communications
https://www.readbyqxmd.com/read/29097440/desensitization-and-tolerance-of-mu-opioid-receptors-on-pontine-kolliker-fuse-neurons
#8
Erica S Levitt, John T Williams
Acute desensitization of mu opioid receptors is thought to be an initial step in the development of tolerance to opioids. Given the resistance of the respiratory system to develop tolerance, desensitization of neurons in the Kölliker-Fuse (KF), a key area in the respiratory circuit, was examined. The activation of G protein-coupled inwardly rectifying potassium (GIRK) current was measured using whole-cell voltage-clamp recordings from KF and locus coeruleus (LC) neurons contained in acute rat brain slices...
November 2, 2017: Molecular Pharmacology
https://www.readbyqxmd.com/read/29074844/limiting-habenular-hyperactivity-ameliorates-maternal-separation-driven-depressive-like-symptoms
#9
Anna Tchenio, Salvatore Lecca, Kristina Valentinova, Manuel Mameli
Early-life stress, including maternal separation (MS), increases the vulnerability to develop mood disorders later in life, but the underlying mechanisms remain elusive. We report that MS promotes depressive-like symptoms in mice at a mature stage of life. Along with this behavioral phenotype, MS drives reduction of GABAB-GIRK signaling and the subsequent lateral habenula (LHb) hyperexcitability-an anatomical substrate devoted to aversive encoding. Attenuating LHb hyperactivity using chemogenetic tools and deep-brain stimulation ameliorates MS depressive-like symptoms...
October 26, 2017: Nature Communications
https://www.readbyqxmd.com/read/29066953/disturbances-in-the-fgfr1-5-ht1a-heteroreceptor-complexes-in-the-raphe-hippocampal-5-ht-system-develop-in-a-genetic-rat-model-of-depression
#10
Dasiel O Borroto-Escuela, Caitlin M DuPont, Xiang Li, David Savelli, Davide Lattanzi, Ipsit Srivastava, Manuel Narváez, Michael Di Palma, Elisa Barbieri, Yuniesky Andrade-Talavera, Riccardo Cuppini, Yuji Odagaki, Miklos Palkovits, Patrizia Ambrogini, Maria Lindskog, Kjell Fuxe
The FGFR1-5-HT1A heteroreceptor complexes are involved in neuroplasticity in the rat hippocampus and in the mesencephalic raphe 5-HT nerve cells. There exists a 5-HT1A protomer enhancement of FGFR1 protomer signaling. Acute and 10 day treatment with intracerebroventricular (i.c.v.) FGF-2 and the 5-HT1A agonist 8-OH-DPAT produced enhanced antidepressant effects in the forced swim test (FST). We studied in the current work the disturbances in the FGFR1-5-HT1A heterocomplexes in a genetic rat model of depression, the Flinders sensitive line (FSL) rats of Sprague-Dawley (SD) origin, by means of neurochemical, neurophysiological and behavioral techniques...
2017: Frontiers in Cellular Neuroscience
https://www.readbyqxmd.com/read/28951616/prolonged-seizure-activity-causes-caspase-dependent-cleavage-and-dysfunction-of-g-protein-activated-inwardly-rectifying-potassium-channels
#11
Brian C Baculis, Amanda C Weiss, Weilun Pang, Han Gil Jeong, Jun Hee Lee, Dai-Chi Liu, Nien-Pei Tsai, Hee Jung Chung
Recurrent high-frequency epileptic seizures cause progressive hippocampal sclerosis, which is associated with caspase-3 activation and NMDA receptor-dependent excitotoxicity. However, the identity of caspase-3 substrates that contribute to seizure-induced hippocampal atrophy remains largely unknown. Here, we show that prolonged high-frequency epileptiform discharges in cultured hippocampal neurons leads to caspase-dependent cleavage of GIRK1 and GIRK2, the major subunits of neuronal G protein-activated inwardly rectifying potassium (GIRK) channels that mediate membrane hyperpolarization and synaptic inhibition in the brain...
September 26, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28935562/n-2-methoxyphenyl-benzenesulfonamide-a-novel-regulator-of-neuronal-g-protein-gated-inward-rectifier-k-channels
#12
Kenneth B Walsh, Elaine A Gay, Bruce E Blough, David W Geurkink
G protein-gated inward rectifier K(+) (GIRK) channels are members of the super-family of proteins known as inward rectifier K(+) (Kir) channels and are expressed throughout the peripheral and central nervous systems. Neuronal GIRK channels are the downstream targets of a number of neuromodulators including opioids, somatostatin, dopamine and cannabinoids. Previous studies have demonstrated that the ATP-sensitive K(+) channel, another member of the Kir channel family, is regulated by sulfonamide drugs. Therefore, to determine if sulfonamides also modulate GIRK channels, we screened a library of arylsulfonamide compounds using a GIRK channel fluorescent assay that utilized pituitary AtT20 cells expressing GIRK channels along with the somatostatin type-2 and -5 receptors...
November 15, 2017: European Journal of Pharmacology
https://www.readbyqxmd.com/read/28895268/lithium-reduces-the-span-of-g-protein-activated-k-girk-channel-inhibition-in-hippocampal-neurons
#13
Nathan Dascal, Moran Rubinstein
OBJECTIVES: Lithium (Li(+) ) is one of the most widely used treatments for bipolar disorder (BD). However, the molecular and neuronal basis of BD, as well as the mechanisms of Li(+) actions are poorly understood. Cellular and biochemical studies identified G proteins as being among the cellular targets for Li(+) action, while genetic studies indicated an association with the KCNJ3 gene, which encodes the G protein-activated inwardly rectifying K(+) (GIRK) channels. GIRK channels regulate neuronal excitability by mediating the inhibitory effects of multiple neurotransmitters and contribute to the resting potassium conductance...
September 12, 2017: Bipolar Disorders
https://www.readbyqxmd.com/read/28826535/functional-selectivity-at-cannabinoid-receptors
#14
Richard Priestley, Michelle Glass, David Kendall
It is now clear that, in contrast to traditional descriptions of G protein-coupled receptor signaling, agonists can activate or inhibit characteristic patterns of downstream effector pathways depending on their structures and the conformational changes induced in the receptor. This is referred to as functional selectivity (also known as agonist-directed trafficking, ligand-induced differential signaling, or biased agonism). It is important because even small structural differences can result in significant variations in overall agonist effects (wanted and unwanted) depending on which postreceptor signaling systems are engaged by each agonist/receptor pairing...
2017: Advances in Pharmacology
https://www.readbyqxmd.com/read/28821664/differential-desensitization-observed-at-multiple-effectors-of-somatic-%C3%AE-opioid-receptors-underlies-sustained-agonist-mediated-inhibition-of-proopiomelanocortin-neuron-activity
#15
Philip D Fox, Shane T Hentges
Activation of somatic μ-opioid receptors (MORs) in hypothalamic proopiomelanocortin (POMC) neurons leads to the activation of G-protein-coupled inward rectifier potassium (GIRK) channels and hyperpolarization, but in response to continued signaling MORs undergo acute desensitization resulting in robust reduction in the peak GIRK current after minutes of agonist exposure. We hypothesized that the attenuation of the GIRK current would lead to a recovery of neuronal excitability whereby desensitization of the receptor would lead to a new steady state of POMC neuron activity reflecting the sustained GIRK current observed after the initial decline from peak with continued agonist exposure...
September 6, 2017: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
https://www.readbyqxmd.com/read/28794459/multiple-excitatory-actions-of-orexins-upon-thalamo-cortical-neurons-in-dorsal-lateral-geniculate-nucleus-implications-for-vision-modulation-by-arousal
#16
Lukasz Chrobok, Katarzyna Palus-Chramiec, Anna Chrzanowska, Mariusz Kepczynski, Marian Henryk Lewandowski
The orexinergic system of the lateral hypothalamus plays a crucial role in maintaining wakefulness and mediating arousal in a circadian time-dependent manner. Due to the extensive connections of orexinergic neurons, both orexins (OXA and OXB) exert mainly excitatory effects upon remote brain areas, including the thalamus. The dorsal lateral geniculate nucleus (DLG) is a relay thalamic centre for the visual system. Its thalamo-cortical (TC) neurons convey photic information from the retina to the primary visual cortex...
August 9, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28755375/ion-channels-as-reporters-of-membrane-receptor-function-automated-analysis-in-xenopus-oocytes
#17
Michel Vivaudou, Zlatomir Todorov, Gina Catalina Reyes-Mejia, Christophe Moreau
G-protein-coupled receptors (GPCR) are the most widely used system of communication used by cells. They sense external signals and translate them into intracellular signals. The information is carried mechanically across the cell membrane, without perturbing its integrity. Agonist binding on the extracellular side causes a change in receptor conformation which propagates to the intracellular side and causes release of activated G-proteins, the first messengers of a variety of signaling cascades.Permitting access to powerful electrophysiological techniques, ion channels can be employed to monitor precisely the most proximal steps of GPCR signaling, receptor conformational changes, and G-protein release...
2017: Methods in Molecular Biology
https://www.readbyqxmd.com/read/28733581/structural-determinants-at-the-m2-muscarinic-receptor-modulate-the-rgs4-girk-response-to-pilocarpine-by-impairment-of-the-receptor-voltage-sensitivity
#18
I-Shan Chen, Kazuharu Furutani, Yoshihisa Kurachi
Membrane potential controls the response of the M2 muscarinic receptor to its ligands. Membrane hyperpolarization increases response to the full agonist acetylcholine (ACh) while decreasing response to the partial agonist pilocarpine. We previously have demonstrated that the regulator of G-protein signaling (RGS) 4 protein discriminates between the voltage-dependent responses of ACh and pilocarpine; however, the underlying mechanism remains unclear. Here we show that RGS4 is involved in the voltage-dependent behavior of the M2 muscarinic receptor-mediated signaling in response to pilocarpine...
July 21, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28724990/large-meta-analysis-of-genome-wide-association-studies-identifies-five-loci-for-lean-body-mass
#19
M Carola Zillikens, Serkalem Demissie, Yi-Hsiang Hsu, Laura M Yerges-Armstrong, Wen-Chi Chou, Lisette Stolk, Gregory Livshits, Linda Broer, Toby Johnson, Daniel L Koller, Zoltán Kutalik, Jian'an Luan, Ida Malkin, Janina S Ried, Albert V Smith, Gudmar Thorleifsson, Liesbeth Vandenput, Jing Hua Zhao, Weihua Zhang, Ali Aghdassi, Kristina Åkesson, Najaf Amin, Leslie J Baier, Inês Barroso, David A Bennett, Lars Bertram, Rainer Biffar, Murielle Bochud, Michael Boehnke, Ingrid B Borecki, Aron S Buchman, Liisa Byberg, Harry Campbell, Natalia Campos Obanda, Jane A Cauley, Peggy M Cawthon, Henna Cederberg, Zhao Chen, Nam H Cho, Hyung Jin Choi, Melina Claussnitzer, Francis Collins, Steven R Cummings, Philip L De Jager, Ilja Demuth, Rosalie A M Dhonukshe-Rutten, Luda Diatchenko, Gudny Eiriksdottir, Anke W Enneman, Mike Erdos, Johan G Eriksson, Joel Eriksson, Karol Estrada, Daniel S Evans, Mary F Feitosa, Mao Fu, Melissa Garcia, Christian Gieger, Thomas Girke, Nicole L Glazer, Harald Grallert, Jagvir Grewal, Bok-Ghee Han, Robert L Hanson, Caroline Hayward, Albert Hofman, Eric P Hoffman, Georg Homuth, Wen-Chi Hsueh, Monica J Hubal, Alan Hubbard, Kim M Huffman, Lise B Husted, Thomas Illig, Erik Ingelsson, Till Ittermann, John-Olov Jansson, Joanne M Jordan, Antti Jula, Magnus Karlsson, Kay-Tee Khaw, Tuomas O Kilpeläinen, Norman Klopp, Jacqueline S L Kloth, Heikki A Koistinen, William E Kraus, Stephen Kritchevsky, Teemu Kuulasmaa, Johanna Kuusisto, Markku Laakso, Jari Lahti, Thomas Lang, Bente L Langdahl, Lenore J Launer, Jong-Young Lee, Markus M Lerch, Joshua R Lewis, Lars Lind, Cecilia Lindgren, Yongmei Liu, Tian Liu, Youfang Liu, Östen Ljunggren, Mattias Lorentzon, Robert N Luben, William Maixner, Fiona E McGuigan, Carolina Medina-Gomez, Thomas Meitinger, Håkan Melhus, Dan Mellström, Simon Melov, Karl Michaëlsson, Braxton D Mitchell, Andrew P Morris, Leif Mosekilde, Anne Newman, Carrie M Nielson, Jeffrey R O'Connell, Ben A Oostra, Eric S Orwoll, Aarno Palotie, Stephen C J Parker, Munro Peacock, Markus Perola, Annette Peters, Ozren Polasek, Richard L Prince, Katri Räikkönen, Stuart H Ralston, Samuli Ripatti, John A Robbins, Jerome I Rotter, Igor Rudan, Veikko Salomaa, Suzanne Satterfield, Eric E Schadt, Sabine Schipf, Laura Scott, Joban Sehmi, Jian Shen, Chan Soo Shin, Gunnar Sigurdsson, Shad Smith, Nicole Soranzo, Alena Stančáková, Elisabeth Steinhagen-Thiessen, Elizabeth A Streeten, Unnur Styrkarsdottir, Karin M A Swart, Sian-Tsung Tan, Mark A Tarnopolsky, Patricia Thompson, Cynthia A Thomson, Unnur Thorsteinsdottir, Emmi Tikkanen, Gregory J Tranah, Jaakko Tuomilehto, Natasja M van Schoor, Arjun Verma, Peter Vollenweider, Henry Völzke, Jean Wactawski-Wende, Mark Walker, Michael N Weedon, Ryan Welch, H-Erich Wichmann, Elisabeth Widen, Frances M K Williams, James F Wilson, Nicole C Wright, Weijia Xie, Lei Yu, Yanhua Zhou, John C Chambers, Angela Döring, Cornelia M van Duijn, Michael J Econs, Vilmundur Gudnason, Jaspal S Kooner, Bruce M Psaty, Timothy D Spector, Kari Stefansson, Fernando Rivadeneira, André G Uitterlinden, Nicholas J Wareham, Vicky Ossowski, Dawn Waterworth, Ruth J F Loos, David Karasik, Tamara B Harris, Claes Ohlsson, Douglas P Kiel
Lean body mass, consisting mostly of skeletal muscle, is important for healthy aging. We performed a genome-wide association study for whole body (20 cohorts of European ancestry with n = 38,292) and appendicular (arms and legs) lean body mass (n = 28,330) measured using dual energy X-ray absorptiometry or bioelectrical impedance analysis, adjusted for sex, age, height, and fat mass. Twenty-one single-nucleotide polymorphisms were significantly associated with lean body mass either genome wide (p < 5 × 10(-8)) or suggestively genome wide (p < 2...
July 19, 2017: Nature Communications
https://www.readbyqxmd.com/read/28720589/dynamic-role-of-the-tether-helix-in-pip2-dependent-gating-of-a-g-protein-gated-potassium-channel
#20
Emre Lacin, Prafulla Aryal, Ian W Glaaser, Karthik Bodhinathan, Eric Tsai, Nidaa Marsh, Stephen J Tucker, Mark S P Sansom, Paul A Slesinger
G protein-gated inwardly rectifying potassium (GIRK) channels control neuronal excitability in the brain and are implicated in several different neurological diseases. The anionic phospholipid phosphatidylinositol 4,5 bisphosphate (PIP2) is an essential cofactor for GIRK channel gating, but the precise mechanism by which PIP2 opens GIRK channels remains poorly understood. Previous structural studies have revealed several highly conserved, positively charged residues in the "tether helix" (C-linker) that interact with the negatively charged PIP2 However, these crystal structures of neuronal GIRK channels in complex with PIP2 provide only snapshots of PIP2's interaction with the channel and thus lack details about the gating transitions triggered by PIP2 binding...
July 18, 2017: Journal of General Physiology
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