Universitat Autònoma de Barcelona. Facultat de Biociències

Viñas Gaza, Helena

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THE HOMEOSTASIS OF SODIUM AND POTASSIUM IN ASTROCYTES, ITS IMPLICATIONS IN INTRACELLULAR SIGNALLING AND UNDER PHTOLOGYCAL CONDITIONSViñas Gaza, Helena | Masgrau Juanola, Roser | Department of Biochemistry and Molecular Biology. Universitat Autònoma de Barcelona.Aims and objectives Contribute to the general understanding of neuroglia and its implications in neurological disorders. Get to know and understand the structure and functions of astrocytes in relation to neurons. Explain the main mechanisms which carry out the Na+/K+ homeostasis. Which channels andtransporters are implicated, their functioning and regulation. Be able to differentiate the homeostasis behaviours under normal circumstances or either underpathological and stressful situations. Establish a relation with a gene mutation that codifies for a subunit of the main Na+/K+ pump with adisease caused by a dysregulation of the astrocytes; familial hemiplegia migraine type II.Neuroglia The brain has de maximum concentration of Na+/K+ATPases which consumes almost the 20% of theenergy required by this organ. This pump is situated in the plasma membrane and it generates theelectrochemical gradient of Na+ and K+. It exports actively 3 molecules of K+ and imports 2 of Na+ thanksto the hydrolysis of one molecule of ATP. The correct gradient is important to buffer the K+ and to providethe energy for the cotransporters and channels of other ions and neurotransmitters.The enzyme has two kinds of sunubits: ɑ-subunit (4 isoforms) containing the binding sites for Na+, K+, ATP and the specific inhibitor ouabain. β-subunit (3 isoforms)There is an additional H+ -binding site located on the C-terminus that further supports the ion transport.Recent studies established the correlation between mutations in the Na+/K+ATPase ɑ isoforms andneurological disorders.Structure of the Na+/K+ATPaseIntroductionNeuroglial cells do not participatedireclty in synaptic interactions andelectrical signalling. They are morenumerous than nerve cells butsmaller and they lack axons anddendrites. There are three types ofglial cells (Figure 1) in the centralnervous system:1. Astrocytes2. Oligodendrocytes• There are four isoforms (ɑ1,ɑ2, ɑ3, ɑ4)• Has three cytoplasmaticdoamins; actuator(A),nucleotide-binding (N)and phosphorylation (P)(Figure 3).ɑ-subunit• It makes direct contact with ɑM7 and ɑM10 of the ɑ-subunit• There are three isoforms (β1, β2, β3).  β-subunitPhysiology of the Na+/K+ATPaseREFERENCES: Bøttger, P., Doğanlı, C. & Lykke-Hartmann, K. Migraine- and dystonia-related disease-mutations of Na+/K+-ATPases: relevance of behavioral studies in mice to disease symptoms and neurological manifestations in humans. Neurosci. Biobehav. Rev. 36, 855–71 (2012).Bernardinelli, Y., Magistretti, P. J. & Chatton, J.-Y. Astrocytes generate Na+-mediated metabolic waves. Proc. Natl. Acad. Sci. U. S. A. 101, 14937–42 (2004).Morth, J. P. et al. The structure of the Na+,K+-ATPase and mapping of isoform differences and disease-related mutations. Philos. Trans. R. Soc. Lond. B. Biol. Sci.364, 217–27 (2009).Kirischuk, S., Parpura, V. & Verkhratsky, A. Sodium dynamics: another key to astroglial excitability? Trends Neurosci. 35, 497–506 (2012).Toustrup-Jensen, M. S. et al. Relationship between intracellular Na+ concentrationand reduced Na+ affinity in Na+,K+-ATPase mutants causing neurological disease. J. Biol. Chem. (2013). doi:10.1074/jbc.M113.543272Familial hemiplegia migraine type II (FHM2)Familial hemiplegic migraine (FHM) is a rare type of migraine with aura. Thereare three types of FHM; type 1 associated with mutations in the neuronal calciumchannels gene (CACNA1A) and is the most prevalent form, type 2 is caused bymutations present in ATP1A2 gene, and type 3 is a rare form of FHM related tomutations in the sodium channel gene (SCN1A).FMH2 is caused by mutations in the ATPS1A2 gene located on the long (q) armof chromosome 1 at position 23.2. The migraine aura is known to be caused bycortical spreading depression (CSD). CSD is a wave of continual strong neuronaldepolarization that slowly progresses across the cortex.There are two hypothesized mechanisms for the effects of ATP1A2 (Gritz &Radcliffe 2013). First, the mutations cause an increase in extracellularpotassium, which can result in the impaired clearance of potassium ions andtherefore induce CSD. Second, since the distribution of ATP1A2 is co-localizedwith the Na+/Ca2+ exchanger, the mutations to ATP1A2 would cause intracellularsodium to increase, which increases intracellular calcium levels through theNa+/Ca2+ exchanger, resulting in glutamate release and a decrease in glutamateclearance and thus lowering the threshold for cortical spreading depression. Bothhypotheses result in making the brain more susceptible to CSD and thereforemigraines with aura.3. MicrogliaAstrocytes contribute to the formation and preservation of a secure blood-brainbarrier. Because of their organization around microvasculature they have amajor role in the supply of glucose. They are a reservoir of glycogen and therare also involved in the control of ionic and osmotic homeostasis as well as inthe removing of several neurotransmitters from the synaptic cleft. They canmodulate the activity of adjacent cells because they are connected to eachother by gap junctions.• It belongs to the FXYD family.• It is not essential for the well funcion of the pump.γ-subunitFigure 1: Schematic representation of nerveand gilial cells. Modified from (Toustrup-Jensen et al. 2013)When stimuli are applied to astrocytes they induce the Ca2+ release from theintracellular stores of the cell. This elevation of Ca2+ is followed by thereleased of glutamate, transiently increasing the effective glutamateconcentration in the synaptic cleft, and ATP.o Glutamate plays an important role in the propagation of the Na+ throughgap junctions (Figure 4).o ATP binds to purinoreceptors on neighbouring astrocytes, which inducethe propagation of Ca2+. The breakdown of ATP will increase glycolysisand uptake of glucose via GLUT-1.The GABA released in the extracellular space is removed by Na+-dependentGAT’s.The Na2+ dependant activation of Na+/K+ ATPase initiates the astrocyte-neurone lactate shuttle (Kirischuk et al. 2012).Intracellular Na+ can affect the functional activity of proteins by bindingdirectly to them.Changes in intracellular Na+ concentration modulate H+/OH-/HCO3- transportsystems, which are fundamental for both intra and extracellular pHhomeostasis.Figure 3. A domain overview ofthe of Na+/K+ ATPase. (Morth etal. 2007)Figure 2: Schematic illustration of the Na+/K+ATPase. (Bøttger et al. 2012)The structure consists of a large catayltic ɑ-subunit which traverses the membrane 10times (ɑM1-ɑM10) and a smallerglycosylated β-subunit.CONCLUSIONS:• Astrocytes are complex cells that respond to a variety of external stimuli. They have to be capable to both perceived andcorrectly respond to those stimuli such as changes in the energy supplies, neuronal activity, changes in the concentration ofions or NT, among others.• The Na+/K+ ATPase pump has a complex expression pattern. Each one of its units has different isoforms related to itslocation and function. Its normal activity is capital to control the homeostasis, mainly of Na+ and K+, but not without affectingthe transients of other ions and NT.• Astrocytes have been found to be implicated in several disorders of the CNS, including FHM2, a rare type of FHM causedby a mutation in the ɑ2 Na+/K+ ATPase.• It would be highly recommendable to go further in research and investigation to contribute to our understanding of astrocytephysiology and its role in neuron-glia interaction under physiological and pathophysiological conditions in the brain.Figure 4: Model for Na+ and metabolic wavetransmission mechanism (Bernardinelli et al.2004)Regulation of extracellular K+homeostasis fundamental .The K+ uptakeby the astrocyte is carried out throughpassive uptake via cotransporters, activeuptake using the Na+/K+ATPase and/orspatial buffering.Astrocytes may also buffer K+ byreleasing K+ directly into the blood stream

The homeostasis of sodium and potassium in astrocytes, its implications in intracellular signalling and under phatologycal conditions

http://ddd.uab.cat/pub/tfg/2014/126370/TFG_HelenaVinasGaza.pdf

The homeostasis of sodium and potassium in astrocytes, its implications in intracellular signalling and under phatologycal conditions

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