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Glia Fiziológia I. Gliotranszmisszió Glia fiziológia I. Gliotranszmisszió Csatornák, receptorok Kapcsoltság, Ca++ Gliotranszmitterek Ioncsatornák Kapcsoltság Nem – vezikuláris release Aquaporinok Glia szincícium Vezikuláris release Neurotransz Gap junctions Transzporterek, egyéb mitter/neuro glia eredetű faktorok modulátor Hemichannels receptorok Gliális neurotranszmitter Asztro network transzporterek Glutamát receptorok térbeli/időbeli szabályozása Glutamát transzporterek GABA receptorok Gliális Ca++, GABA transzporterek Citokin és kemokin Ca++ hullámok receptorok Glycin transzporterek Endotelin Egyéb transzporterek receptorok Ozmolitikumok Komplement Glia eredetű neuropeptidek rendszer Glia eredetű Purinoreceptorok növekedési faktorok Glia fiziológia Gliális neurotranszmitter transzporterek Glutamát transzporterek asztrocitákban EAA- Excitatory Amino Acid Transporter (EAAT) család GLAST asztroglia, radiális glián (EAAT1) GLT1 (EAAT2) főleg asztroglia, de bizonyos neuronokon is EAAC1 (EAAT3) érett neuronok EAAT4 Purkinje sejtek, GABA-erg interneuronok, retina EAAT5 retina bipoláris és fotoreceptor sejtjei GLAST: Glutamate Aspartate Transporter GLT1: fő glu trporter az agyban GLT1: Glutamate Transporter 1 EAAC1: Excitatory Amino Acid Carrier 1 [Glu]EC: 1-5 uM (ez megnő persze neuron-tüzeléskor, akár több száz uM-ra (??)) [Glu]IC: 1-10 mM tehát Glu eltávolítás az ec. térből nagy koncentráció-gradienssel szemben kell, hogy történjen ! („uphill” translocation) GLUTAMÁT EXCITOTOXICITÁS GLUTAMÁT receptor overstimuláció Ca++ overload neuronpusztulás https://www.slideshare.net/shashikantbhargava/glutamate-seminar conditional GLT-1 knock-out mouse to uncover cell-type- specific functional roles of GLT1 elimination of GLT-1 from astrocytes : EEG spike-trains from GLT-1 KO • loss of ∼80% of GLT-1 protein and of glutamate uptake activity • excess mortality, lower body weight, and seizures ! An increase in the ratio of cellular excitation to inhibition (E/I ratio) has been proposed to underlie the pathogenesis of neuropsychiatric disorders, such as autism spectrum disorders (ASD), obsessive-compulsive disorder (OCD), and Tourette's syndrome (TS). In astrocyte-specific GLT1 inducible knockout (GLAST(CreERT2/+)/GLT1(flox/flox), iKO) mice: • pathological repetitive behaviors including excessive and injurious levels of self- grooming and tic-like head shakes • NMDA receptor antagonist ameliorated the pathological repetitive behaviors Glia fiziológia Gliális neurotranszmitter transzporterek Glutamát transzporterek asztrocitákban + K ec: ~2-2,5 mM + Na ec: ~130 mM ++ Ca ec: ~1.5-2 mM Cl- : ~100 mM be: 1 Glu-, 3 Na+, 1H+ ec ki: 1 K+ ionok koncentráció- gradiensük szerint mozognak glia + alacsony Na ic fenntartása kritikus a Glutamát elektrogén a transzporter mert uptake szempontjából !! ! befelé irányuló áram van és depolarizáció: a benti + töltés tovább segíti a – glutamát „uphill” felvételét Glia fiziológia Gliális neurotranszmitter transzporterek Glutamát transzporterek szerepe asztrocitákban Glutamát: sokféle ionmozgást okoz asztroban K+ Na+ be: 1Glu- AMPAR aktiváció: 3Na+, 1H+ be: Na+ ki: K+ + 1. Na+/K+ pumpa eredmény: net Na influx 2. Na+/Ca++ exchanger Na+ ~5-10mM 20-30 mM-ra nő ki: Na+ be: K+ ic (NCX) gyors megfordulása: energiaigényes és ki: Na+ be: Ca++ !!! lassabb ezt ellensúlyozza 1. és 2. Glia fiziológia Gliális neurotranszmitter transzporterek ! Glutamát transzporterek asztrocitákban + + + alacsony Na ic fenntartása glutamát transzport a Na /K kritikus a Glutamát pumpa működése miatt energiagényes : uptake szempontjából !! 1 glu = 1.5 ATP ha asztro energiája kevés és Na+/K+ homeosztázis felborul asztro nem tud glutamátot eltávolítani ! sőt !!! ilyenkor a gliális Glu-transzporter működése meg is fordulhat de NCX „reverz” módja javíthat a helyzeten ! ki: Na+ be: Ca++ (asztron relatíve magas excitotoxicitás denzitásban van NCX) Glia fiziológia Gliális neurotranszmitter transzporterek GABA transzporterek asztrocitákban nem annyira fontosak asztroban mint glutamát-transzporterek, mert a GABA neuronális visszavétele sokkal nagyobb mértékű, mint glutamáté GABA transporter type 1 (GAT1 – főleg neuron) mindhárom GAT GABA transporter type 2 (GAT2 – liver, kidney, leptomeninges) lehet asztroban is GABA transporter type 3 (GAT3 – főleg asztro) - HC, cortex asztroban főleg GAT3 - Bergmann gliában GAT1 http://www.csupomona.edu/~seskandari/ Glia fiziológia Gliális neurotranszmitter transzporterek + GABA transzporterek asztrocitákban K ec: ~2-2,5 mMglia + Na ec: ~130 mM ++ Ca ec: ~1.5-2 mM - be: Cl ec: ~100 mM 1 GABA és 2 Na+ Na+ elektrokémiai gradiense szerint glia GAD: Glutamát dehidrogenáz Remember: - - GABAA akitvációra neuronba Cl influx és hiperpolarizáció - - gliában GABAA akitváció: Cl efflux és depolarizáció glutamate uptake-induced release of GABA from astrocytes has a direct impact on the excitability of pyramidal neurons in the hippocampus • GABA transzporter megfordulásával GABA ürül asztrocitákból • GABA ürülését glutamát uptake blokkolásával gátolni lehet, tehát • a Glu transporter aktivitás triggereli a GABA transzporter megfordulását (valszeg az ic. Na+ szint növelésén keresztül) • az asztroból ürülő GABA hozzájárul a neuronok aktivitás-függő tónikus gátlásához The results suggest the existence of a novel molecular mechanism by which astrocytes transform glutamatergic excitation into GABAergic inhibition providing an adjustable, in situ negative feedback on the excitability of neurons. Glia fiziológia Gliális neurotranszmitter transzporterek Glycin transzporterek asztrocitákban Glycin: - gátló neurotranszmitter főleg gerincvelőben, agytörzsben, retinában - ugyanakkor glutamát ko-agonistája NMDA receptorokon: serkentő NT GlyT1 transzporter: GlyT2 transzporter: asztrocitákon főleg neuronokon be: 1 glycin, 2Na+, 1 Cl- be: 1 glycin, 3Na+, 1 Cl- Gliális GlyT1 reverzál potenciálja nagyon közel van a nyugalmi membrán- potenciáljához: kis depolarizációra könnyen megfordulhat: nem vezikuláris gly release Eulenburg 2005 Glia fiziológia Gliális neurotranszmitter transzporterek Gly Glycin transzporterek/receptorok receptorokról glycinerg nem beszéltünk korábban NMDAR ko-agonista Ca++ Eulenburg 2005 hiperpolarizáció Localization and proposed functions of GlyTs at excitatory and inhibitory synapses. At inhibitory synapses, glycine release from the presynaptic terminal activates postsynaptic GlyRs and thereby induces ClK influx – hyperpolarization – of the postsynaptic cell. At excitatory glutamatergic synapses, glycine acts as an essential co-agonist of postsynaptic NMDARs, whereas neighbouring glutamate receptors of the a-amino-3-hydroxy-5-methyl-4-isoxazole- propionic-acid receptor (AMPAR) subtype require only glutamate for channel activation. Here, glycine might be derived from neighbouring glycinergic terminals or even be released from astrocytes via non-vesicular mechanisms (e.g. reverse transport by GlyT1). GlyT2 is localized in the presynaptic plasma membrane of glycinergic neurons and transports glycine into the terminal, thereby enabling the refilling of synaptic vesicles with glycine by the HC- dependent vesicular inhibitory amino acid transporter (VIAAT). GlyT1 is mainly expressed by glia cells surrounding both inhibitory and excitatory synapses. In addition, GlyT1 has been found on terminals of some excitatory neurons. Thus, GlyT1 mediates the clearance of glycine from the synaptic cleft of inhibitory synapses and, in addition, participates in the regulation of the glycine concentrations at excitatory synapses. D-serine glycin Now glycine is viewed to team up together with D-serine but also with kynurenic acid to regulate the functionality of different subsets of receptors at a single locus. .. patch-clamp biosensor method to confirm the glycine release from astrocytes by using GlyRα1 and Glyβ-expressing HEK293T cells ... Glia fiziológia Gliális neurotranszmitter transzporterek Egyéb transzporterek asztrocitákban - sokféle más transzporter is lehet asztroban – attól függ, milyen neuron szomszédja ! dopamin – transzporterek asztro monoamin-szint norepinephrine - transzporterek szabályozásban betöltött szerepe szerotonin – transzporterek még elég kérdéses ???? hisztamin – transzporterek taurin – transzporterek (forward-uptake vagy reverse-release) Glia fiziológia Gliális neurotranszmitter transzporterek Egyéb transzporterek asztrocitákban Taurine = 2-aminoethanesulfonic acid, nem ionos ozmolit DIDS: 4,4'- diisothiocyanostilbene-2,2'- disulfonic acid Taurine has many fundamental biological roles such as conjugation of bile acids, antioxidation, osmoregulation, membrane stabilization and modulation of calcium signaling. It is essential for cardiovascular function, and development and function of skeletal muscle, the retina and the central nervous system. http://www2.imbf.ku.dk/CellSignalling/IHLambert/ Ozmolitikumok = ozmózist befolyásoló anyagok Osmolalitás: szárazanyag- Ozmolitikumok („osmolytes”): koncentráció / kg víz - elektrolitok, melyek magas koncentrációban Osmolaritás: szárazanyag- vannak jelen a citoszolban és ec. térben: pl. koncentráció / l víz Na+, K+, Cl- Ozmotikus nyomás: szérum, - kis szerves molekulák: aminosavak és emlős sejt: származékaik (taurine, glutamate, glutamine, 300 mOsm/kg (szűk határok, glycine, GABA and N-acetylaspartate) 275-310 mOsm/kg) - polyalkoholok (myoinositol, sorbitol) - aminok (glycerophosphoryl choline, betaine, creatine/P-creatine and phosphoethanolamine) Az agyban a legfontosabbak: - glutamate, myo-inositol, creatine, taurine és N-acetylaspartate - glutamate van a legnagyobb koncentrációban ezek között - taurine a rágcsáló
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