title: Neurological disease mutations of α3 Na+,K+-ATPase: Structural and functional perspectives and rescue of compromised function.
abstract: Na+,K+-ATPase creates transmembrane ion gradients crucial to the function of the central nervous system. The α-subunit of Na+,K+-ATPase exists as four isoforms (α1-α4). Several neurological phenotypes derive from α3 mutations. The effects of some of these mutations on Na+,K+-ATPase function have been studied in vitro. Here we discuss the α3 disease mutations as well as information derived from studies of corresponding mutations of α1 in the light of the high-resolution crystal structures of the Na+,K+-ATPase. A high proportion of the α3 disease mutations occur in the transmembrane sector and nearby regions essential to Na+and K+binding. In several cases the compromised function can be traced to disturbance of the Na+specific binding site III. Recently, a secondary mutation was found to rescue the defective Na+binding caused by a disease mutation. A perspective is that it may be possible to develop an efficient pharmaceutical mimicking the rescuing effect.
authors: Department of Biomedicine, Aarhus University, 8000 Aarhus C, Denmark. Electronic address: rhj@biomed.au.dk.
authors: Rikke
authors: R
authors: Holm
authors: Department of Biomedicine, Aarhus University, 8000 Aarhus C, Denmark. Electronic address: mtj@biomed.au.dk.
authors: Mads S
authors: MS
authors: Toustrup-Jensen
authors: Department of Biomedicine, Aarhus University, 8000 Aarhus C, Denmark. Electronic address: ape@biomed.au.dk.
authors: Anja P
authors: AP
authors: Einholm
authors: Department of Biomedicine, Aarhus University, 8000 Aarhus C, Denmark. Electronic address: vs@biomed.au.dk.
authors: Vivien R
authors: VR
authors: Schack
authors: Department of Biomedicine, Aarhus University, 8000 Aarhus C, Denmark. Electronic address: jpa@biomed.au.dk.
authors: Jens P
authors: JP
authors: Andersen
authors: Department of Biomedicine, Aarhus University, 8000 Aarhus C, Denmark. Electronic address: bv@biomed.au.dk.
authors: Bente
authors: B
authors: Vilsen
mesh_terms: D000818:Animals; D006801:Humans; D056004:Molecular Dynamics Simulation; D009154:Mutation; D019636:Neurodegenerative Diseases / Q000235:genetics* / Q000378:metabolism; D010641:Phenotype; D000254:Sodium-Potassium-Exchanging ATPase / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism
chemical_list: D000254:Sodium-Potassium-Exchanging ATPase
keywords: Alternating hemiplegia of childhood (AHC); Na(+) site; Na(+),K(+)-pump; Protein structure; Rapid-onset dystonia parkinsonism (RDP); Second-site mutation