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Insights into the Pathology of the α3 Na(+)/K(+)-ATPase Ion Pump in Neurological Disorders; Lessons from Animal Models.

ABSTRACT: The transmembrane Na(+)-/K(+) ATPase is located at the plasma membrane of all mammalian cells. The Na(+)-/K(+) ATPase utilizes energy from ATP hydrolysis to extrude three Na(+) cations and import two K(+) cations into the cell. The minimum constellation for an active Na(+)-/K(+) ATPase is one alpha (α) and one beta (β) subunit. Mammals express four α isoforms (α1-4), encoded by the ATP1A1-4 genes, respectively. The α1 isoform is ubiquitously expressed in the adult central nervous system (CNS) whereas α2 primarily is expressed in astrocytes and α3 in neurons. Na(+) and K(+) are the principal ions involved in action potential propagation during neuronal depolarization. The α1 and α3 Na(+)-/K(+) ATPases are therefore prime candidates for restoring neuronal membrane potential after depolarization and for maintaining neuronal excitability. The α3 isoform has approximately four-fold lower Na(+) affinity compared to α1 and is specifically required for rapid restoration of large transient increases in [Na(+)]i. Conditions associated with α3 deficiency are therefore likely aggravated by suprathreshold neuronal activity. The α3 isoform been suggested to support re-uptake of neurotransmitters. These processes are required for normal brain activity, and in fact autosomal dominant de novo mutations in ATP1A3 encoding the α3 isoform has been found to cause the three neurological diseases Rapid Onset Dystonia Parkinsonism (RDP), Alternating Hemiplegia of Childhood (AHC), and Cerebellar ataxia, areflexia, pes cavus, optic atrophy, and sensorineural hearing loss (CAPOS). All three diseases cause acute onset of neurological symptoms, but the predominant neurological manifestations differ with particularly early onset of hemiplegic/dystonic episodes and mental decline in AHC, ataxic encephalopathy and impairment of vision and hearing in CAPOS syndrome and late onset of dystonia/parkinsonism in RDP. Several mouse models have been generated to study the in vivo consequences of Atp1a3 modulation. The different mice show varying degrees of hyperactivity, gait problems, and learning disability as well as stress-induced seizures. With the advent of several Atp1a3-gene or chemically modified animal models that closely phenocopy many aspects of the human disorders, we will be able to reach a much better understanding of the etiology of RDP, AHC, and CAPOS syndrome.

SUBMITTER: Holm TH

PROVIDER: S-EPMC4906016 | biostudies-other | 2016

REPOSITORIES: biostudies-other

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Insights into the Pathology of the α3 Na(+)/K(+)-ATPase Ion Pump in Neurological Disorders; Lessons from Animal Models.

Holm Thomas H TH Lykke-Hartmann Karin K

Frontiers in physiology 20160614

The transmembrane Na(+)-/K(+) ATPase is located at the plasma membrane of all mammalian cells. The Na(+)-/K(+) ATPase utilizes energy from ATP hydrolysis to extrude three Na(+) cations and import two K(+) cations into the cell. The minimum constellation for an active Na(+)-/K(+) ATPase is one alpha (α) and one beta (β) subunit. Mammals express four α isoforms (α1-4), encoded by the ATP1A1-4 genes, respectively. The α1 isoform is ubiquitously expressed in the adult central nervous system (CNS) wh ...[more]

PMID: 27378932

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Project description:The Na(+),K(+)-ATPase pump achieves thermodynamically uphill exchange of cytoplasmic Na(+) ions for extracellular K(+) ions by using ATP-mediated phosphorylation, followed by autodephosphorylation, to power conformational changes that allow ion access to the pump's binding sites from only one side of the membrane at a time. Formally, the pump behaves like an ion channel with two tightly coupled gates that are constrained to open and close alternately. The marine agent palytoxin disrupts this coupling, allowing both gates to sometimes be open, so temporarily transforming a pump into an ion channel. We made a cysteine scan of Na(+),K(+)-ATPase transmembrane (TM) segments TM1 to TM6, and used recordings of Na(+) current flow through palytoxin-bound pump-channels to monitor accessibility of introduced cysteine residues via their reaction with hydrophilic methanethiosulfonate (MTS) reagents. To visualize the open-channel pathway, the reactive positions were mapped onto a homology model of Na(+),K(+)-ATPase based on the structure of the related sarcoplasmicand endoplasmic-reticulum (SERCA) Ca(2+)-ATPase in a BeF(3)(-)-trapped state,(1,2) in which the extra-cytoplasmic gate is wide open (although the cytoplasmic access pathway is firmly shut). The results revealed a single unbroken chain of reactive positions that traverses the pump from the extracellular surface to the cytoplasm, comprises residues from TM1, TM2, TM4 and TM6, and passes through the equivalent of cation binding site II in SERCA, but not through site I. Cavity search analysis of the homology model validated its use for mapping the data by yielding a calculated extra-cytoplasmic pathway surrounded by MTS-reactive residues. As predicted by previous experimental results, that calculated extra-cytoplasmic pathway abruptly broadens above residue T806, at the outermost end of TM6 that forms the floor of the extracellular-facing vestibule. These findings provide a structural basis for further understanding cation translocation by the Na(+),K(+)-ATPase and by other P-type pumps like the Ca(2+)- and H(+),K(+)-ATPases.

Project description:Decades ago, it was proposed that Na transport in cardiac myocytes is modulated by large changes in cytoplasmic Na concentration within restricted subsarcolemmal spaces. Here, we probe this hypothesis for Na/K pumps by generating constitutive transsarcolemmal Na flux with the Na channel opener veratridine in whole-cell patch-clamp recordings. Using 25 mM Na in the patch pipette, pump currents decay strongly during continuous activation by extracellular K (?, ?2 s). In contradiction to depletion hypotheses, the decay becomes stronger when pump currents are decreased by hyperpolarization. Na channel currents are nearly unchanged by pump activity in these conditions, and conversely, continuous Na currents up to 0.5 nA in magnitude have negligible effects on pump currents. These outcomes are even more pronounced using 50 mM Li as a cytoplasmic Na congener. Thus, the Na/K pump current decay reflects mostly an inactivation mechanism that immobilizes Na/K pump charge movements, not cytoplasmic Na depletion. When channel currents are increased beyond 1 nA, models with unrestricted subsarcolemmal diffusion accurately predict current decay (? ?15 s) and reversal potential shifts observed for Na, Li, and K currents through Na channels opened by veratridine, as well as for Na, K, Cs, Li, and Cl currents recorded in nystatin-permeabilized myocytes. Ion concentrations in the pipette tip (i.e., access conductance) track without appreciable delay the current changes caused by sarcolemmal ion flux. Importantly, cytoplasmic mixing volumes, calculated from current decay kinetics, increase and decrease as expected with osmolarity changes (? >30 s). Na/K pump current run-down over 20 min reflects a failure of pumps to recover from inactivation. Simulations reveal that pump inactivation coupled with Na-activated recovery enhances the rapidity and effectivity of Na homeostasis in cardiac myocytes. In conclusion, an autoregulatory mechanism enhances cardiac Na/K pump activity when cytoplasmic Na rises and suppresses pump activity when cytoplasmic Na declines.

Dataset Information

Insights into the Pathology of the α3 Na(+)/K(+)-ATPase Ion Pump in Neurological Disorders; Lessons from Animal Models.

Publications

Insights into the Pathology of the α3 Na(+)/K(+)-ATPase Ion Pump in Neurological Disorders; Lessons from Animal Models.

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