Tissue-specific regulation of the Na, K-ATPase by the cytosolic NaAF: some thoughts on brain function

Abstract

The dual topology P-2 ATPase, which consists of a α²β² tetramer, explains numerous functions of the cation transporting ATPase system. The ubiquitous cytosolic protein regulator (NaAF) of 170 k Da mass regulates P-2 ATPase function in a low Ca (µM) neighborhood where Ca acts as the terminal regulator in the intracellular signaling cascade. The Na, K- ATPase also seems to function as an H, K-ATPase or a Ca-ATPase in altered states based on the local environment (low pH or high Ca) in a tissue specific manner. These altered effects are analogous to that of the 80 k Da cytosolic HAF in regulating the gastric H, K-ATPase system of the parietal cells.  However there are some important differences. The HAF stimulates the Na, K-ATPase but the NaAF cannot stimulate H, K-ATPase. Also, HAF is as effective as NaAF in stimulating the kidney Na, K-ATPase but about 60% as effective in stimulating brain Na, K-ATPase. These observations reveal that the Na, K- ATPase systems from kidney and brain, consisting of different kinds of αβ–isoforms, interact differently with the HAF molecule; thus substantiating that P-2 ATPase system plays different roles in different tissues in response to an universal NaAF. Another rare feature of the HAF is that it has histone kinase activity, suggesting that the HAF and NaAF may be capable of sending a direct signal to the nucleus for gene expression.In this paper, the central role of the NaAF-regulated Na, K-ATPase system in the activity and function of brain tissue is discussed.  It is noted that the altered function of the nerve terminus located Na, K-ATPase system works as a Ca-pump (after depolarization) and as a Na-pump (in repolarization) in alternate sequence. The possible role of Ca-sensing receptor (CaR) in the voltage gated channeling of Ca has been raised and the possibility of a dual channel Na/H antiporter (NhaA) in pH homeostasis is discussed.