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From the University of Florida College of Medicine and the Department of Veterans Affairs Medical Center, Gainesville, Florida, and the Keck School of Medicine of the University of Southern California, Los Angeles, California.
Grant Support: By National Institutes of Health grants R01 DK47981 and R01 DK075065 (Dr. Kone), R01 DK49750 and the Department of Veterans Affairs (Dr. Wingo), R01 DK34316 (Dr. McDonough), and R21 DK080233 (Dr. Youn).
Potential Financial Conflicts of Interest: None disclosed.
Requests for Single Reprints: Bruce C. Kone, MD, University of Florida College of Medicine, 1600 Southwest Archer Road, Gainesville, FL 32610; e-mail, firstname.lastname@example.org.
Current Author Addresses: Ms. Greenlee and Drs. Wingo and Kone: University of Florida College of Medicine, 1600 Southwest Archer Road, Gainesville, FL 32610.
Drs. McDonough and Youn: University of Southern California Keck School of Medicine, 1333 San Pablo Street, Los Angeles, CA 90089.
Humans are intermittently exposed to large variations in potassium intake, which range from periods of fasting to ingestion of potassium-rich meals. These fluctuations would abruptly alter plasma potassium concentration if not for rapid mechanisms, primarily in skeletal muscle and the liver, that buffer the changes in plasma potassium concentration by means of transcellular potassium redistribution and feedback control of renal potassium excretion. However, buffers have capacity limits, and even robust feedback control mechanisms require that the perturbation occur before feedback can initiate corrective action. In contrast, feedforward control mechanisms sense the effect of disturbances on the system's homeostasis. This review highlights recent experimental insights into the participation of feedback and feedforward control mechanisms in potassium homeostasis. New data make clear that feedforward homeostatic responses activate when decreased potassium intake is sensed, even when plasma potassium concentration is still within the normal range and before frank hypokalemia ensues, in addition to the classic feedback activation of renal potassium conservation when plasma potassium concentration decreases. Given the clinical importance of dyskalemias in patients, these novel experimental paradigms invite renewed clinical inquiry into this important area.
CNS = central nervous system. Left. Classic mechanisms. Right. Additional putative mechanisms.
We present a simplified model of potassium handling by collecting duct cell types. Principal cells in the collecting duct are responsible for secretion of excess potassium in the circulation into the tubule lumen and thus into the urine. This secretion is accomplished by luminal membrane potassium channels responding primarily to the electrochemical gradient for potassium generated by the combined actions of the basolateral membrane Na,K-ATPase and a luminal membrane sodium channel (the target of the potassium-sparing diuretic amiloride). In states of potassium depletion, potassium secretion by the principal cells is inhibited and the luminal membrane H,K-ATPase is activated in the intercalated cells to reclaim the potassium that remains in the tubular fluid, thereby limiting urinary potassium wasting. ADP = adenosine diphosphate; ATP = adenosine triphosphate; CCD = cortical collecting duct; DT = distal tubule; Glom = glomerulus; IMCD = inner medullary collecting duct; MTAL = medullary thick ascending limb of Henle loop; OMCD = outer medullary collecting duct; Pi = inorganic phosphate.
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