Genomes and Genes
Gene Symbol: Galphai
Description: G protein alpha i subunit
Alias: CG10060, DG[[alpha1]], DGalpha1, Dmel\CG10060, G-alpha-65A, G-ia65A, G-ialpha65A, G-ialpha65a, G-oalpha65A, GNAI1/2/3, G[[alphai]], G[[i]]alpha, Gai, Galpha i, Galpha65A, Galpha[[i65A]], Galpha[[i]], Galpha[[i]]65A, Galphai/o, Galphaiota65A, Gi-alpha, Gi/0, Gialpha, galphai, G protein alpha i subunit, CG10060-PA, G protein I a-subunit 65A, G protein alpha o subunit 65A, G protein alpha subunit, G protein alpha-subunit, G protein alphai subunit, G protein alphai subunit 65A, G protein alphao subunit 65A, Galphai-PA
Species: fruit fly
- Izumi Y, Ohta N, Itoh Furuya A, Fuse N, Matsuzaki F. Differential functions of G protein and Baz-aPKC signaling pathways in Drosophila neuroblast asymmetric division. J Cell Biol. 2004;164:729-38 pubmed..In Ggamma1 and Gbeta13F mutant NBs, Pins-Galphai, which normally localize in the apical cortex, no longer distribute asymmetrically...
- Johnston C, Hirono K, Prehoda K, Doe C. Identification of an Aurora-A/PinsLINKER/Dlg spindle orientation pathway using induced cell polarity in S2 cells. Cell. 2009;138:1150-63 pubmed publisher..This "induced cortical polarity" assay is suitable for rapid identification of the proteins, domains, and amino acids regulating spindle orientation or cell polarity. ..
- Siller K, Cabernard C, Doe C. The NuMA-related Mud protein binds Pins and regulates spindle orientation in Drosophila neuroblasts. Nat Cell Biol. 2006;8:594-600 pubmed..We propose that Mud is a functional orthologue of mammalian NuMA and Caenorhabditis elegans Lin-5, and that Mud coordinates spindle orientation with cortical polarity to promote asymmetric cell division. ..
- Kopein D, Katanaev V. Drosophila GoLoco-protein Pins is a target of Galpha(o)-mediated G protein-coupled receptor signaling. Mol Biol Cell. 2009;20:3865-77 pubmed publisher..g., in the context of the nervous system development, where Galpha(o) acts downstream from Frizzled and redundantly with Galpha(i) to control the asymmetry of cell divisions. ..
- Kaltschmidt J, Brand A. Asymmetric cell division: microtubule dynamics and spindle asymmetry. J Cell Sci. 2002;115:2257-64 pubmed..In this commentary we discuss recent findings on how the mitotic spindle is positioned and on cleavage site induction and place them in the context of cell size asymmetry in different model organisms. ..
- Nipper R, Siller K, Smith N, Doe C, Prehoda K. Galphai generates multiple Pins activation states to link cortical polarity and spindle orientation in Drosophila neuroblasts. Proc Natl Acad Sci U S A. 2007;104:14306-11 pubmed..Neuroblasts asymmetrically localize Galphai, Pins, and Mud proteins; Pins/Galphai direct cortical polarity, whereas Mud is required for spindle orientation...
- Siegrist S, Doe C. Microtubule-induced Pins/Galphai cortical polarity in Drosophila neuroblasts. Cell. 2005;123:1323-35 pubmed..We show that astral microtubules, kinesin Khc-73, and Discs large (Dlg) induce cortical polarization of Pins/Galphai in Drosophila neuroblasts; this cortical domain is functional for generating spindle asymmetry, daughter-cell-..
- Ogden S, Fei D, Schilling N, Ahmed Y, Hwa J, Robbins D. G protein Galphai functions immediately downstream of Smoothened in Hedgehog signalling. Nature. 2008;456:967-70 pubmed publisher..Our results demonstrate that Smo functions as a canonical GPCR, which signals through Galphai to regulate Hh pathway activation.
- Wang H, Ng K, Qian H, Siderovski D, Chia W, Yu F. Ric-8 controls Drosophila neural progenitor asymmetric division by regulating heterotrimeric G proteins. Nat Cell Biol. 2005;7:1091-8 pubmed..Ric-8 is necessary for membrane targeting of Galphai, Pins and Gbeta13F, presumably by regulating multiple Galpha subunit(s)...
- Schwabe T, Bainton R, Fetter R, Heberlein U, Gaul U. GPCR signaling is required for blood-brain barrier formation in drosophila. Cell. 2005;123:133-44 pubmed..Our study demonstrates the importance of morphogenetic regulation in blood-brain barrier development and places GPCR signaling at its core. ..
- Betschinger J, Knoblich J. Dare to be different: asymmetric cell division in Drosophila, C. elegans and vertebrates. Curr Biol. 2004;14:R674-85 pubmed..Here, we outline the steps and factors that are involved in this process in Drosophila and C. elegans and discuss their potential conservation in vertebrates. ..
- Boto T, Gomez Diaz C, Alcorta E. Expression analysis of the 3 G-protein subunits, Galpha, Gbeta, and Ggamma, in the olfactory receptor organs of adult Drosophila melanogaster. Chem Senses. 2010;35:183-93 pubmed publisher..Finally, complete coexpression was found between Gi and Gq, which are mediators of the cyclic adenosine monophosphate and IP3 transduction cascades, respectively. ..
- Hampoelz B, Hoeller O, Bowman S, Dunican D, Knoblich J. Drosophila Ric-8 is essential for plasma-membrane localization of heterotrimeric G proteins. Nat Cell Biol. 2005;7:1099-105 pubmed..Ric-8 is a cytoplasmic protein that binds both the GDP- and GTP-bound form of the G-protein alpha-subunit Galphai. In ric-8 mutants, neither Galphai nor its associated beta-subunit Gbeta13F are localized at the plasma membrane, ..
- Bredendiek N, Hütte J, Steingräber A, Hatt H, Gisselmann G, Neuhaus E. Go ? is involved in sugar perception in Drosophila. Chem Senses. 2011;36:69-81 pubmed publisher..Because the perception of other sweet stimuli was not affected by mutations in Go?, we also found strong indication for the existence of multiple signaling pathways in the insect gustatory system. ..
- Albertson R, Doe C. Dlg, Scrib and Lgl regulate neuroblast cell size and mitotic spindle asymmetry. Nat Cell Biol. 2003;5:166-70 pubmed..We conclude that Dlg/Scrib/Lgl are important in regulating cortical polarity, cell size asymmetry and mitotic spindle asymmetry in Drosophila neuroblasts. ..
- Cheng S, Maier D, Hipfner D. Drosophila G-protein-coupled receptor kinase 2 regulates cAMP-dependent Hedgehog signaling. Development. 2012;139:85-94 pubmed publisher..Gprk2 is important for normal cAMP regulation, and thus has an indirect effect on the activity of Pka-regulated components of the Hh pathway, including Smo itself. ..
- Bowman S, Neumüller R, Novatchkova M, Du Q, Knoblich J. The Drosophila NuMA Homolog Mud regulates spindle orientation in asymmetric cell division. Dev Cell. 2006;10:731-42 pubmed..Our data suggest a model in which asymmetrically localized Pins-G alphai complexes regulate spindle orientation by directly binding to Mud. ..
- Katanayeva N, Kopein D, Portmann R, Hess D, Katanaev V. Competing activities of heterotrimeric G proteins in Drosophila wing maturation. PLoS ONE. 2010;5:e12331 pubmed publisher..Our results provide a comprehensive functional analysis of the heterotrimeric G protein proteome in the late stages of Drosophila wing development. ..
- Deng Y, Zhang W, Farhat K, Oberland S, Gisselmann G, Neuhaus E. The stimulatory G?(s) protein is involved in olfactory signal transduction in Drosophila. PLoS ONE. 2011;6:e18605 pubmed publisher..Together, we provide evidence that G?(s) plays a role in the OR mediated signaling cascade in Drosophila. ..
- Izumi Y, Ohta N, Hisata K, Raabe T, Matsuzaki F. Drosophila Pins-binding protein Mud regulates spindle-polarity coupling and centrosome organization. Nat Cell Biol. 2006;8:586-93 pubmed..We propose that Drosophila Mud, vertebrate NuMA and Caenorhabditis elegans Lin-5 (refs 5, 6) have conserved roles in the mechanism by which G-proteins regulate the mitotic spindle. ..
- Schaefer M, Shevchenko A, Knoblich J. A protein complex containing Inscuteable and the Galpha-binding protein Pins orients asymmetric cell divisions in Drosophila. Curr Biol. 2000;10:353-62 pubmed
- Speicher S, Fischer A, Knoblich J, Carmena A. The PDZ protein Canoe regulates the asymmetric division of Drosophila neuroblasts and muscle progenitors. Curr Biol. 2008;18:831-7 pubmed publisher..show that Cno functions as a new effector of the apical proteins Inscuteable (Insc)-Partner of Inscuteable (Pins)-Galphai during the asymmetric division of Drosophila neuroblasts (NBs)...
- Katanaev V, Tomlinson A. Dual roles for the trimeric G protein Go in asymmetric cell division in Drosophila. Proc Natl Acad Sci U S A. 2006;103:6524-9 pubmed..Thus, Go likely integrates the signaling that directs the formation of the complex with the signaling that directs where the complex forms. ..
- Fuse N, Hisata K, Katzen A, Matsuzaki F. Heterotrimeric G proteins regulate daughter cell size asymmetry in Drosophila neuroblast divisions. Curr Biol. 2003;13:947-54 pubmed..Furthermore, the multiple equal cleavages of G beta mutant neuroblasts accompany neural defects; this finding suggests indispensable roles of eccentric division in assuring the stem cell properties of neuroblasts. ..
- Parmentier M, Woods D, Greig S, Phan P, Radovic A, Bryant P, et al. Rapsynoid/partner of inscuteable controls asymmetric division of larval neuroblasts in Drosophila. J Neurosci. 2000;20:RC84 pubmed..Our data show that Raps is a novel protein involved in the control of asymmetric divisions of neuroblasts. ..
- Lai E, Orgogozo V. A hidden program in Drosophila peripheral neurogenesis revealed: fundamental principles underlying sensory organ diversity. Dev Biol. 2004;269:1-17 pubmed..We propose that most Drosophila sensory organs are built from an archetypal lineage, and we speculate about how this stereotyped pattern of cell divisions may have been built during evolution...
- Hampoelz B, Knoblich J. Heterotrimeric G proteins: new tricks for an old dog. Cell. 2004;119:453-6 pubmed..2004), and Current Biology (Couwenbergs et al., 2004) show that this function is conserved in vertebrates and--like the classical pathway--involves cycling of G proteins between GDP and GTP bound conformations. ..
- Koon A, Budnik V. Inhibitory control of synaptic and behavioral plasticity by octopaminergic signaling. J Neurosci. 2012;32:6312-22 pubmed publisher..These results demonstrate the dual action of octopamine on synaptic growth and behavioral plasticity, and highlight the important role of inhibitory influences for normal responses to physiological stimuli. ..
- Lee C, Andersen R, Cabernard C, Manning L, Tran K, Lanskey M, et al. Drosophila Aurora-A kinase inhibits neuroblast self-renewal by regulating aPKC/Numb cortical polarity and spindle orientation. Genes Dev. 2006;20:3464-74 pubmed..We conclude that Aurora-A and Numb are novel inhibitors of neuroblast self-renewal and that spindle orientation regulates neuroblast self-renewal. ..
- Ragkousi K, Gibson M. Cell division and the maintenance of epithelial order. J Cell Biol. 2014;207:181-8 pubmed publisher..These studies reveal how symmetrically dividing cells both exploit and conform to tissue organization to orient their mitotic spindles during division and establish new adhesive junctions during cytokinesis. ..
- Taniguchi K, Kokuryo A, Imano T, Minami R, Nakagoshi H, Adachi Yamada T. Isoform-specific functions of Mud/NuMA mediate binucleation of Drosophila male accessory gland cells. BMC Dev Biol. 2014;14:46 pubmed publisher..We also propose that Mud(S) is a key regulator triggering cytokinesis skipping in binucleation processes. ..
- Hutterer A, Berdnik D, Wirtz Peitz F, Zigman M, Schleiffer A, Knoblich J. Mitotic activation of the kinase Aurora-A requires its binding partner Bora. Dev Cell. 2006;11:147-57 pubmed..We propose a model in which activation of Cdc2 initiates the release of Bora into the cytoplasm where it can bind and activate Aurora-A. ..
- Connell M, Cabernard C, Ricketson D, Doe C, Prehoda K. Asymmetric cortical extension shifts cleavage furrow position in Drosophila neuroblasts. Mol Biol Cell. 2011;22:4220-6 pubmed publisher..We propose a model in which contraction-driven asymmetric polar extension of the neuroblast cortex during anaphase contributes to asymmetric furrow position and daughter cell size. ..
- Hong S, Lee K, Kwak S, Kim A, Bai H, Jung M, et al. Minibrain/Dyrk1a regulates food intake through the Sir2-FOXO-sNPF/NPY pathway in Drosophila and mammals. PLoS Genet. 2012;8:e1002857 pubmed publisher..Our findings demonstrate that Mnb/Dyrk1a regulates food intake through the evolutionary conserved Sir2-FOXO-sNPF/NPY pathway in Drosophila melanogaster and mammals...
- Ignatious Raja J, Katanayeva N, Katanaev V, Galizia C. Role of Go/i subgroup of G proteins in olfactory signaling of Drosophila melanogaster. Eur J Neurosci. 2014;39:1245-55 pubmed publisher..We propose a transduction cascade model involving several parallel processes, in which the metabotropic component is activated by Go and Gi , and uses G??. ..
- Naganos S, Ueno K, Horiuchi J, Saitoe M. Learning defects in Drosophila growth restricted chico mutants are caused by attenuated adenylyl cyclase activity. Mol Brain. 2016;9:37 pubmed publisher..Our results suggest that some cognitive defects associated with reduced IIS may occur, independently of developmental defects, from acute reductions in cAMP signaling. ..
- Bonaccorsi S, Mottier V, Giansanti M, Bolkan B, Williams B, Goldberg M, et al. The Drosophila Lkb1 kinase is required for spindle formation and asymmetric neuroblast division. Development. 2007;134:2183-93 pubmed..unequal cytokinesis, abrogate proper localization of Bazooka, Par-6, DaPKC and Miranda, but affect neither Pins/Galphai localization nor spindle rotation...
- Chen Y, Jiang J. Decoding the phosphorylation code in Hedgehog signal transduction. Cell Res. 2013;23:186-200 pubmed publisher..In this review, we focus on the multifaceted roles that phosphorylation plays in Hh signal transduction, and discuss the conservation and difference between Drosophila and mammalian Hh signaling mechanisms. ..
- Boyle M, French R, Cosand K, Dorman J, Kiehart D, Berg C. Division of labor: subsets of dorsal-appendage-forming cells control the shape of the entire tube. Dev Biol. 2010;346:68-79 pubmed publisher..Gbeta mutant floor cells are unable to control the width of the appendage while Gbeta mutant leading roof cells fail to direct the elongation of the appendage and the convergent-extension of the roof-cell population. ..
- Wolfgang W, Forte M. Posterior localization of the Drosophila Gi alpha protein during early embryogenesis requires a subset of the posterior group genes. Int J Dev Biol. 1995;39:581-6 pubmedShortly after fertilization in Drosophila embryos, the G-protein alpha subunit, Gi alpha, undergoes a dramatic redistribution...
- Chai P, Liu Z, Chia W, Cai Y. Hedgehog signaling acts with the temporal cascade to promote neuroblast cell cycle exit. PLoS Biol. 2013;11:e1001494 pubmed publisher..Interestingly, hh is likely a target of Castor. Hence, Hh signaling provides a link between the temporal series and the asymmetric division machinery in scheduling the end of neurogenesis. ..
- Schmidt C, Garen Fazio S, Chow Y, Neer E. Neuronal expression of a newly identified Drosophila melanogaster G protein alpha 0 subunit. Cell Regul. 1989;1:125-34 pubmed..DG alpha 0 message and protein were also detected in the antennae, oocytes, and ovarian nurse cells. The neuronal expression of this gene is similar to mammalian alpha 0, which is most abundantly expressed in the brain. ..
- Guo F, Yi W, Zhou M, Guo A. Go signaling in mushroom bodies regulates sleep in Drosophila. Sleep. 2011;34:273-81 pubmed..Genetic interaction results showed that Go signaling serves as a neuronal transmission inhibitor in a cAMP-independent pathway. Go signaling is a novel signaling pathway in MBs that regulates sleep in Drosophila. ..
- Yu F, Morin X, Kaushik R, Bahri S, Yang X, Chia W. A mouse homologue of Drosophila pins can asymmetrically localize and substitute for pins function in Drosophila neuroblasts. J Cell Sci. 2003;116:887-96 pubmed..requires an apically localized protein complex that includes Inscuteable, Pins, Bazooka, DmPar-6, DaPKC and Galphai. Pins acts to stabilize the apical complex during neuroblast divisions...
- Tuxworth R, Chia W. Asymmetric cell division: Miranda chauffeured by Jaguar?. Mol Cell. 2003;11:288-9 pubmed..An intact F-actin cytoskeleton was known to be required, and now a myosin VI (Jaguar) has been shown to be necessary for basal targeting of cell fate determinants in neuroblasts. ..
- GONCZY P. Mechanisms of spindle positioning: focus on flies and worms. Trends Cell Biol. 2002;12:332-9 pubmed..This article discusses recent findings that indicate how this mechanism might be used for spindle positioning during Drosophila and Caenorhabditis elegans development. ..
- Devambez I, Ali Agha M, Mitri C, Bockaert J, Parmentier M, Marion Poll F, et al. G?o is required for L-canavanine detection in Drosophila. PLoS ONE. 2013;8:e63484 pubmed publisher..In conclusion, our study revealed that G?o47A plays a crucial role in L-canavanine detection. ..
- Yoshiura S, Ohta N, Matsuzaki F. Tre1 GPCR signaling orients stem cell divisions in the Drosophila central nervous system. Dev Cell. 2012;22:79-91 pubmed publisher..Given the universal role of the Par complex in cellular polarization, we propose that the GPCR-Pins system is a comprehensive mechanism controlling tissue polarity by orienting polarized stem cells and their divisions. ..
- Bosveld F, Markova O, Guirao B, Martin C, Wang Z, Pierre A, et al. Epithelial tricellular junctions act as interphase cell shape sensors to orient mitosis. Nature. 2016;530:495-8 pubmed publisher..Thus, in addition to their function as epithelial barrier structures, TCJs serve as polarity cues promoting geometry and mechanical sensing in epithelial tissues. ..
- Moorhouse K, Burgess D. How to be at the right place at the right time: the importance of spindle positioning in embryos. Mol Reprod Dev. 2014;81:884-95 pubmed publisher..The data generated from these model organisms have made unique contributions to our knowledge of spindle positioning. Future work will address how all of these different factors work together to regulate the position of the spindle. ..
- Krishnan A, Mustafa A, AlmÃ©n M, Fredriksson R, Williams M, SchiÃ¶th H. Evolutionary hierarchy of vertebrate-like heterotrimeric G protein families. Mol Phylogenet Evol. 2015;91:27-40 pubmed publisher..Our robust classification/hierarchy is essential to further understand the differential roles of GPCR/G protein mediated intracellular signaling system across various metazoan lineages. ..
- Saini N, Reichert H. Neural stem cells in Drosophila: molecular genetic mechanisms underlying normal neural proliferation and abnormal brain tumor formation. Stem Cells Int. 2012;2012:486169 pubmed publisher..These cellular and molecular findings in Drosophila are likely to provide valuable genetic links for analyzing mammalian neural stem cells and tumor biology. ..
- Smith N, Prehoda K. Robust spindle alignment in Drosophila neuroblasts by ultrasensitive activation of pins. Mol Cell. 2011;43:540-9 pubmed publisher..Many signaling proteins contain multiple protein interaction domains, and the decoy mechanism may be a common method for generating ultrasensitivity in regulatory pathways. ..
- Ahringer J. Control of cell polarity and mitotic spindle positioning in animal cells. Curr Opin Cell Biol. 2003;15:73-81 pubmed..Microtubules and conserved PAR proteins are essential mediators of cell polarity, and mitotic spindle positioning depends on heterotrimeric G protein signalling and the microtubule motor protein dynein. ..
- Yang M, Nelson D, Funakoshi Y, Padgett R. Genome-wide microarray analysis of TGFbeta signaling in the Drosophila brain. BMC Dev Biol. 2004;4:14 pubmed..Many of these genes are novel and several genes are implicated in growth control. Among the genes regulated by both pathways is ultraspiracle, which further connects TGFbeta with neuronal remodeling. ..
- Li H, Chaney S, Roberts I, Forte M, Hirsh J. Ectopic G-protein expression in dopamine and serotonin neurons blocks cocaine sensitization in Drosophila melanogaster. Curr Biol. 2000;10:211-4 pubmed..Finally, repeated drug stimulation of a nerve cord preparation that is postsynaptic to the brain amine cells failed to induce sensitization, further showing the importance of presynaptic modulation in sensitization. ..
- Mauser J, Prehoda K. Inscuteable regulates the Pins-Mud spindle orientation pathway. PLoS ONE. 2012;7:e29611 pubmed publisher..Insc-regulated complex assembly may ensure that the spindle is attached to the cortex (via Dlg) before activation of spindle pulling forces by Dynein/Dynactin (via Mud). ..
- Kronen M, Schoenfelder K, Klein A, Nystul T. Basolateral junction proteins regulate competition for the follicle stem cell niche in the Drosophila ovary. PLoS ONE. 2014;9:e101085 pubmed publisher..In addition, we demonstrate that the neutral drift model can be adapted to quantify non-neutral behavior of mutant clones. ..
- Ren G, Folke J, Hauser F, Li S, Grimmelikhuijzen C. The A- and B-type muscarinic acetylcholine receptors from Drosophila melanogaster couple to different second messenger pathways. Biochem Biophys Res Commun. 2015;462:358-64 pubmed publisher..Furthermore, in protostomes, probably all A-type mAChRs are coupled to Gq/11 and all B-type mAChRs to G0/i. ..
- David N, Martin C, Segalen M, Rosenfeld F, Schweisguth F, Bellaiche Y. Drosophila Ric-8 regulates Galphai cortical localization to promote Galphai-dependent planar orientation of the mitotic spindle during asymmetric cell division. Nat Cell Biol. 2005;7:1083-90 pubmed..pl) is polarized along the antero-posterior axis by Frizzled signalling and, during this division, activation of Galphai depends on Partner of Inscuteable (Pins)...
- Knust E. G protein signaling and asymmetric cell division. Cell. 2001;107:125-8 pubmed..Receptor-independent activation of heterotrimeric G proteins by the Drosophila GoLoco protein Partner of Inscuteable seems to represent a novel mechanism to control these events. ..
- Mauri F, Reichardt I, Mummery Widmer J, Yamazaki M, Knoblich J. The conserved discs-large binding partner Banderuola regulates asymmetric cell division in Drosophila. Curr Biol. 2014;24:1811-25 pubmed publisher..Bnd has an antioncogenic function that is redundant with Dlg, and the physical interaction between the two proteins is conserved in evolution. ..
- Lin Y, Parikh H, Park Y. Loco signaling pathway in longevity. Small Gtpases. 2011;2:158-161 pubmed..Consistently, our data showed that downregulation of Loco significantly diminishes cAMP amounts and increases p-ERK levels with higher resistance to the oxidative stress. ..
- Besson C, Bernard F, Corson F, Rouault H, Reynaud E, Keder A, et al. Planar Cell Polarity Breaks the Symmetry of PAR Protein Distribution prior to Mitosis in Drosophila Sensory Organ Precursor Cells. Curr Biol. 2015;25:1104-10 pubmed publisher..This study therefore identifies PCP as the initial symmetry-breaking signal for the planar polarization of PAR proteins in asymmetrically dividing SOPs. ..
- Schweisguth F. Cell polarity: fixing cell polarity with Pins. Curr Biol. 2000;10:R265-7 pubmed..A protein complex is assembled in a step-wise manner at the apical pole of Drosophila neuroblasts. This complex organizes the apical-basal polarity of asymmetrically dividing neuroblasts, and may act via G-protein signalling. ..
- Granderath S, Stollewerk A, Greig S, Goodman C, O Kane C, Klämbt C. loco encodes an RGS protein required for Drosophila glial differentiation. Development. 1999;126:1781-91 pubmed..Strikingly, the interaction is not confined to the RGS domain. This interaction and the coexpression of LOCO and Galphai suggests a function of G-protein signalling for glial cell development.
- Ahringer J. Playing ping pong with pins: cortical and microtubule-induced polarity. Cell. 2005;123:1184-6 pubmed..In this issue of Cell, it is turned around and shown that the transfer of polarity information between the cortex and the spindle is not just one way. In Drosophila neuroblasts, the spindle also has polarizing activity on the cortex. ..