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Glia Fiziológia Gliális Neurotranszmitter Transzporterek

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Glia Fiziológia Gliális Neurotranszmitter Transzporterek 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: Glutamate Transporter 1 EAAC1: Excitatory Amino Acid Carrier 1 [Glu]EC: 2-5 uM (ez megnő persze neuron-tüzeléskor) [Glu]IC: 1-10 mM tehát Glu eltávolítás nagy koncentráció-gradienssel szemben kell, hogy történjen ! („uphill” translocation) Glia fiziológia Gliális neurotranszmitter transzporterek Glutamát transzporterek asztrocitákban be: 1 Glu-, 3 Na+, 1H+ glia ki: 1 K+ ionok koncentráció- gradiensük szerint mozognak alacsony Na+ic fenntartása kritikus a Glutamát elektrogén a transzporter mert uptake szempontjából !!! befelé irányuló áram van és deploarizáció: a benti + töltés tovább segíti a – glutamát felvételét Glia fiziológia Gliális neurotranszmitter transzporterek Glutamát transzporterek asztrocitákban Glutamát: sokféle ionmozgást okoz asztroban be: 1Glu- AMPAR aktiváció: 3Na+, 1H+ be: Na+ ki: K+ 1. Na+/K+ pumpa eredmény: net Na+ influx 2. Na+/Ca++ exchanger Na+ ~5mM 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 transzporter működése meg is fordulhat de NCX „reverz” módja javíthat a helyzeten ! ki: Na+ be: Ca++ (asztrocitán 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) mindhárom van asztroban GABA transporter type 2 (GAT2) - HC, cortex asztroban főleg GAT3 GABA transporter type 3 (GAT3) - Bergmann gliában GAT1 http://www.csupomona.edu/~seskandari/ Glia fiziológia Gliális neurotranszmitter transzporterek GABA transzporterek asztrocitákban glia be: 1 GABA és 2 Na+ Na+ elektrokémiai gradiense szerint - GABAA akitvációra neuronba Cl- influx és hiperpolarizáció - - gliában GABAA akitváció: Cl efflux és depolarizáció 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 Glycin transzporterek asztrocitákban glycinerg 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. 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) Taurine = 2-aminoethanesulfonic acid, nem ionos ozmolit, szerves sav 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 DIDS: 4,4'- central nervous system. diisothiocyanostilbene-2,2'- disulfonic acid http://www2.imbf.ku.dk/CellSignalling/IHLambert/ Ozmolitikumok („osmolytes”): Osmolalitás: szárazanyag- koncentráció / kg víz - elektrolitok, melyek magas koncentrációban Osmolaritás: szárazanyag- vannak jelen a citoszolban és ec. térben: pl. koncentráció / l víz + + - Na , K , Cl Osmotikus nyomás: szérum, - kis szerves molekulák: aminosavak és emlős sejt: származékaik (taurine, glutamate, glycine, GABA 300 mOsm/kg (szűk határok, 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 agyban nagy koncentrációjú, de macska vagy emberi agyban szintje alacsonyabb (ezekben a fajokban a szintézise csak kismértékű) Glia fiziológia Glia eredetű neuropeptidek - minden glia-típus képes termelésükre erősen régió-specifikusan és a fejlődés során változó módon - neuropeptid release: mechanizmus még elég tisztázatlan pl. asztro opioid termelése : osztódás és dendritnövekedés szab. pl. asztro ANP és angitoenzin termelése: agyi víz 2007 Butt Verkhratsky homeosztázis szabályozása pl. asztro VIP termelése: agyi mikrocirkuláció szab. pl. ONEC sejt NPY termelése: axonnövekedés szabályozása olf. bulbusba Glia fiziológia Neurotophinok neuronális fejlődést, túlélést, funkcionálást támogatják Glia eredetű NGF (nerve growth factor) növekedési BDNF (brain derived neurotrophic factor) faktorok NT-3, NT4 (neurotrophinok) Fiziológiás hatások Patológiás hatások neuronális differenciáció neuronális regeneráció fejlődés repair növekedés migráció pathfinding szinaptogenezis szinaptikus remodelling Főleg asztrociták termelnek sokféle növekedési faktort ODG kevesebbet – de pl. netrin-1-et igen (ezt asztro nem expresszálja) – axon pathfinding Glia fiziológia I. Gliotranszmisszió Csatornák, receptorok Kapcsoltság, Ca++ Gliotranszmitterek Ioncsatornák Kapcsoltság Nem – vezikuláris release Aquaporinok Glia szincícium/network 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 Purinoreceptorok Ca++ hullámok Glycin transzporterek Endotelin receptorok Egyéb transzporterek Ozmolitikumok Citokin és kemokin receptorok Glia eredetű neuropeptidek Komplement Glia eredetű rendszer növekedési faktorok Glia fiziológia II. Agyi homeosztázis szabályozása Ion-homeosztázis az extracelluláris térben „K+ spatial buffering” [Glu]ec szabályozása Retina, K+ siphoning Ammónia Extracellular space [GABA]ec szabályozása Cl- homeosztázis Víz - homeosztázis Ca++ homeosztázis szabályozása pH szabályozás Swelling AsztroGlia fiziológia Ion-homeosztázis az extracelluláris térben A fő ion-transzport rendszerek asztrocitákban 3.előadás ODC-nél tárgyaltuk Please recall your memories on neuronal firing…. …in about 1865 the first recordings of the time course of the action potential were made.. (ideg-izom prepik)… AsztroGlia fiziológia Ion-homeosztázis az extracelluláris térben Intra- + + Extracelluláris celluláris K ic: ~100-140 mM K ec: ~2-2,5 mM + + agyi környezet Na ic: <10 mM Na ec: ~130 mM ++ ++ Ca ic: <0,0001 mM Ca ec: ~1.5-2 mM - - Cl ic: ~30-40 mM (glia) Cl ec: ~100 mM - Cl ic: ~2-10 mM (neuron) Neuronok: Na+, Ca++ influx: depolarizáció K+ efflux: repolarizáció Glia ! Neuron is ! EC térben relatíve alacsony a K+ spatial [K+], kicsi a térfogat - kis K+ Klorid- Na+/K+ATPáz redistribution release is nagy változást okoz kapcsolt K+ uptake Ha EC térben [K+] magas a K+ efflux lassul, repolarizáció nem tökéletes K+ -t el kell távolítani !! neuron depolarizált lesz, Na+ ec csatornák inaktiválódnak „conduction block” AsztroGlia fiziológia „K+ spatial buffering” K+ térbeli pufferelés 1960, Stephen William
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