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- Title
Targeted Mutations in the Na,K-ATPase Alpha 2 Isoform Confer Ouabain Resistance and Result in Abnormal Behavior in Mice.
- Authors
SCHAEFER, TORI L.; LINGREL, JERRY B.; MOSELEY, AMY E.; VORHEES, CHARLES V.; WILLIAMS, MICHAEL T.
- Abstract
Sodium and potassium-activated adenosine triphosphatases (Na,KATPase) are ubiquitous, participate in osmotic balance and membrane potential, and are composed of α, β, and γ subunits. The α subunit is required for the catalytic and transport properties of the enzyme and contains binding sites for cations, ATP, and digitalis-like compounds including ouabain. There are four known a isoforms; three that are expressed in the CNS in a regional and cell-specific manner. The α2 isoform is most commonly found in astrocytes, pyramidal cells of the hippocampus in adults, and developmentally in several other neuronal types. Ouabain-like compounds are thought to be produced endogenously in mammals, bind the Na,K-ATPase, and function as a stress-related hormone, however, the impact of the Na,K-ATPase ouabain binding site on neurobehavioral function is largely unknown. To determine if the ouabain binding site of the α2 isoform plays a physiological role in CNS function, we examined knock-in mice in which the normally ouabain-sensitive α2 isoform was made resistant (a2R/R) while still retaining basal Na,KATPase enzymatic function. Egocentric learning (Cincinnati water maze) was impaired in adult α2R/R mice compared to wild type (WT) mice. They also exhibited decreased locomotor activity in a novel environment and increased responsiveness to a challenge with an indirect sympathomimetic agonist (methamphetamine) relative to WT mice. The α2R/R mice also demonstrated a blunted acoustic startle reflex and a failure to habituate to repeated acoustic stimuli. The α2R/R mice showed no evidence of altered anxiety (elevated zero maze) nor were they impaired in spatial learning or memory in the Morris water maze and neither group could learn in a large Morris maze. These results suggest that the ouabain binding site is involved in specific types of learning and the modulation of dopamine-mediated locomotor behavior.
- Subjects
ADENOSINE triphosphatase; DOPAMINE; CENTRAL nervous system; LABORATORY mice; GENETIC mutation; LEARNING
- Publication
Synapse, 2011, Vol 65, Issue 6, p520
- ISSN
0887-4476
- Publication type
Article
- DOI
10.1002/syn.20870