Region‐ and neuronal‐subtype‐specific expression of Na,K‐ATPase alpha and beta subunit isoforms in the mouse brain

Abstract

Na,K‐ATPase is a ubiquitous molecule contributing to the asymmetrical distribution of Na+ and K+ ions across the plasma membrane and maintenance of the membrane potential, a prerequisite of neuronal activity. Na,K‐ATPase comprises three subunits (α, β, and FXYD). The α subunit has four isoforms in mice, with three of them (α1, α2, and α3) expressed in the brain. However, the functional and biological significances of the different brain isoforms remain to be fully elucidated. Recent studies have revealed the association of Atp1a3, a gene encoding α3 subunit, with neurological disorders. To map the cellular distributions of the α subunit isoforms and their coexpression patterns, we evaluated the mRNA expression of Atp1a1, Atp1a2, and Atp1a3 by in situ hybridization in the mouse brain. Atp1a1 and Atp1a3 were expressed in neurons, whereas Atp1a2 was almost exclusively expressed in glial cells. Most neurons coexpressed Atp1a1 and Atp1a3, with highly heterogeneous expression levels across the brain regions and neuronal subtypes. We identified parvalbumin (PV)‐expressing GABAergic neurons in the hippocampus, somatosensory cortex, and retrosplenial cortex as an example of a neuronal subtype expressing low Atp1a1 and high Atp1a3. The expression of Atp1b isoforms was also heterogeneous across brain regions and cellular subtypes. The PV‐expressing neurons expressed a high level of Atp1b1 and a low level of Atp1b2 and Atp1b3. These findings provide basic information on the region‐ and neuronal‐subtype‐dependent expression of Na,K‐ATPase α and β subunit isoforms, as well as a rationale for the selective involvement of neurons expressing high levels of Atp1a3 in neurological disorders.

An interaction between PRRT2 and Na+/K+ ATPase contributes to the control of neuronal excitability

“…Over time, more than 50% of these patients develop epilepsy, in addition to their episodic movement disorders. These clinical manifestations involve diverse brain areas, such as hippocampus, cerebral cortex, basal ganglia and cerebellum, all regions where PRRT2 and α3-NKA are co-expressed 11 , 50 . Recently, both genes were linked to network alterations in the cerebellum that generate similar dystonic phenotypes 1 , 11 , 12 , 51 – 55 .…”

Multi‐angle development of therapeutic methods for Alzheimer's disease

“…Therefore, identifying neurons that are critically dependent on NAKα3 might help in identifying the vulnerable neuronal populations in neurological/neurodegenerative disorders, as well as in understanding the physiological significance of selective NAK isozyme usage for neuronal functions. To elucidate whether and how individual neurons use specific isoforms of the α and β subunits, we performed in situ analyses of mouse whole brain (Murata et al, 2020). We employed a double‐fluorescence in situ hybridization technique with digoxigenin‐ and fluorescein (FLU)‐labelled probes to evaluate the expression of both α1 and α3 in the same tissue slice (Murata et al, 2020).…”

“…This deep region is where we observed neuronal loss associated with amylospheroid accumulation (Figure 3d). Parvalbumin neurons are somatic inhibitory interneurons that target the perisomatic domain of pyramidal cells and regulate the generation of Na + -dependent action potentials there (Buhl, Halasy, & Somogyi, 1994;Knowles & Schwartzkroin, 1981;Miles, Toth, Gulyas, Hajos, & Freund, 1996). A single parvalbumin neuron innervates hundreds of pyramidal neurons (Halasy, Buhl, Lorinczi, Tamas, & Somogyi, 1996;Sik, Penttonen, Ylinen, & Buzsaki, 1995;Somogyi, Nunzi, Gorio, & Smith, 1983).…”

“…To elucidate whether and how individual neurons use specific isoforms of the α and β subunits, we performed in situ analyses of mouse whole brain (Murata et al, 2020). We employed a double‐fluorescence in situ hybridization technique with digoxigenin‐ and fluorescein (FLU)‐labelled probes to evaluate the expression of both α1 and α3 in the same tissue slice (Murata et al, 2020). As shown in a representative image, both α1 ( Atp1a1 ) and α3 ( Atp1a3 ) were expressed in all six layers of the cortex (Figure 3c).…”

“…Mechanism of neurodegeneration induced by the amylospheroid (ASPD)/NAKα3 interaction (a and b are modified from Ohnishi et al, 2015, and c is modified from Murata et al, 2020). (d) Sagittal sections of 5xFAD mice at 6 months of age were stained with anti‐ASPD‐specific rpASD1 antibody or anti‐NeuN antibody, as shown by Noguchi et al (2009).…”