Cellular mechanisms for bi-directional 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-directional control of tubular sodium transporters by natriuretic and antinatriuretic factors. The model is based on experimental data from studies on the regulation of the activity of Na+,K+-ATPase, the enzyme that provides the electrochemical gradient necessary for tubular reabsorption of electrolytes and solutes in all tubular segments. Regulation is carried out to a large extent by autocrine and paracrine factors. Of particular interest are the two catecholamines, dopamine and norepinephrine. Dopamine is produced in proximal tubular cells and inhibits Na+,K+-ATPase activity in several tubule segments. Renal dopamine availability is regulated by the degrading enzyme, catechol-O-methyl transferase. Renal sympathetic nerve endings contain norepinephrine and neuropeptide Y (NPY). Activation of alpha-adrenergic receptors increase and activation of beta-adrenergic receptors decrease Na+,K+-ATPase activity. alpha-Adrenergic stimulation increases the Na+ affinity of the enzyme and thereby the driving force for transcellular Na+ transport. NPY acts as a master hormone by synergizing the alpha- and antagonizing the 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 phosphatases, 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 protein kinase A and C have been identified and their functional significance has been verified.
Aperia
A
A
Department of Woman And Child Health, St. Göran's Children's Hospital, Karolinska Institute, Stockholm, Sweden.
Fryckstedt
J
J
Holtbäck
U
U
Belusa
R
R
Cheng
X J
XJ
Eklöf
A C
AC
Li
D
D
Wang
Z M
ZM
Ohtomo
Y
Y
D000818:Animals; D001692:Biological Transport / Q000502:physiology; D006801:Humans; D007684:Kidney Tubules / Q000166:cytology* / Q000378:metabolism*; D012964:Sodium / Q000378:metabolism*
D012964:Sodium