CELLULAR MECHANISMS FOR BIDIRECTIONAL REGULATION OF TUBULAR SODIUM-REABSORPTION

The molecular mechanisms underlying the regulation of sodium excretion are incompletely known. Here we propose a general model for a bi-dire ctional control of tubular sodium transporters by natriuretic and anti natriuretic factors. The model is based on experimental data from stud ies on the regulation of the activity of Na+,K+-ATPase, the enzyme tha t provides the electrochemical gradient necessary for tubular reabsorp tion of electrolytes and solutes in all tubular segments. Regulation i s carried out to a large extent by autocrine and paracrine factors. Of particular interest are the two catecholamines, dopamine and norepine phrine. Dopamine is produced in proximal tubular cells and inhibits Na +,K+-ATPase activity in several tubule segments. Renal dopamine availa bility is regulated by the degrading enzyme, catechol-O-methyl transfe rase. Renal sympathetic nerve endings contain norepinephrine and neuro peptide Y (NPY). Activation of alpha-adrenergic receptors increase and activation of beta-adrenergic receptors decrease Na+,K+-ATPase activi ty. alpha-Adrenergic stimulation increases the Na+ affinity of the enz yme and thereby the driving force for transcellular Na+ transport. NPY acts as a master hormone by synergizing the alpha- and antagonizing t he beta-adrenergic effects. Dopamine and norepinephrine control Na+,K-ATPase activity by exerting opposing forces on a common intracellular signaling system of second messengers, protein kinases and protein ph osphatases, ultimately determining the phosphorylation state of Na+,K-ATPase and thereby its activity. Important crossroads in this network are localized and functionally defined. Phosphorylation sites for pro tein kinase A and C have been identified and their functional signific ance has been verified.