Extracellular fluid (ECF) +} must be maintained within a narrow range. If ECF +] falls too low (hypokalemia), cell membranes hyperpolarize, and if ECF +] increases too much (hyperkalemia) cell membranes depobrize, both disrupt normal electrical excitability and can have life threatening cardiac effects. Kidneys and muscle work in concert to maintain ECF ]. During hypokalemia muscle ICF K is redistributed to buffer the fall in ECF }. During hyperkalemia K+ is pumped into muscle ICF until renal adjustments can occur. These important muscle specific homeostatic processes are only beginning to be understood at the molecular level. Evidence supports the hypothesis that K loss from muscle during hypokalemia results from decreased active K+ influx mediated by sodium pump (Na,KATPase, NKA) inhibition, and that K+ uptake during hyperktilemia is mediated by sodium pump activation. Our lab has established that during low K+ diet abundance of NKA subunits are depressed in an isoform and muscle specific manner: 60-95 percent fall in a2, not a 1. Using a novel K+ clamp technique, we recently showed that early in K+ restriction, prior to fall in a2, there is a severe blunting of both insulin stimulated K+ uptake, and of insulin stimulated redistribution of NKA ct2 type pumps from endosomes to the plasma membrane (PM). Evidence is mounting that the bumetanide sensitive Na,K,2C1 cotransporter also accounts for a component of muscle K+ influx and, thus, could play a role in potassium homeostasis. The overall aims are to determine the molecular mechanisms responsible for tapping muscle K+ stores during hypokalemia, for clearing excess plasma +] into the ICF store after K+ restoration, and to understand how these processes are altered in a set of clinically relevant paradigms. The contribution of both Na,K-ATPase isoforms and NKCCI in both red oxidative white glycolytic muscle will be studied with a compartmental analysis approach in which the following are assessed: whole body K+ uptake, muscle specific K+ transport, subcellular distribution and activity of K+ transporters, and pool size regulation of K transporter protein and mRNA levels.
Aim 1 will test the hypothesis that the shift of K+ to ECF during K restriction is mediated by decreased plasma membrane (PM) expression of both NKA a2 and NKCC1 coupled to resistance to insulin stimulated K+ uptake, and that this process is altered in uremia accompanying chronic renal failure.
Aim 2 will test the hypothesis that thyroid hormone or dexamethasone, both of which increase NKA cx2 (and perhaps NKCC 1), alter extrarenal control of K+ horneostasis.
Aim 3 will test the hypothesis that the uptake of K+ from ECF to ICF during K+ restoration (following K+ restriction) is mediated by normalizing surface expression of both NKA a2 and NKCC1. Accomplishing these aims will identify the cellular mechanisms responsible for tapping and repleting the muscle K+ reservoir, which will, ideally, suggest strategies to manipulate muscle K stores in clinical settings.
| Youn, Jang H; McDonough, Alicia A (2009) Recent advances in understanding integrative control of potassium homeostasis. Annu Rev Physiol 71:381-401 |
| Hauck, Christian; Potter, Tatjana; Bartz, Michaela et al. (2009) Isoform specificity of cardiac glycosides binding to human Na+,K+-ATPase alpha1beta1, alpha2beta1 and alpha3beta1. Eur J Pharmacol 622:7-14 |
| Greenlee, Megan; Wingo, Charles S; McDonough, Alicia A et al. (2009) Narrative review: evolving concepts in potassium homeostasis and hypokalemia. Ann Intern Med 150:619-25 |
| Zheng, Dan; Perianayagam, Anjana; Lee, Donna H et al. (2008) AMPK activation with AICAR provokes an acute fall in plasma [K+]. Am J Physiol Cell Physiol 294:C126-35 |
| Lee, Felix N; Oh, Gisuk; McDonough, Alicia A et al. (2007) Evidence for gut factor in K+ homeostasis. Am J Physiol Renal Physiol 293:F541-7 |
| Chen, Pei; Guzman, John P; Leong, Patrick K K et al. (2006) Modest dietary K+ restriction provokes insulin resistance of cellular K+ uptake and phosphorylation of renal outer medulla K+ channel without fall in plasma K+ concentration. Am J Physiol Cell Physiol 290:C1355-63 |
| McDonough, Alicia A; Youn, Jang H (2005) Role of muscle in regulating extracellular [K+]. Semin Nephrol 25:335-42 |
| Rhee, Michael S; Perianayagam, Anjana; Chen, Pei et al. (2004) Dexamethasone treatment causes resistance to insulin-stimulated cellular potassium uptake in the rat. Am J Physiol Cell Physiol 287:C1229-37 |
| Yang, Li E; Leong, Patrick K K; Guzman, Juan P et al. (2003) Modest K+ restriction provokes insulin resistance of cellular K+ uptake without decrease in plasma K. Ann N Y Acad Sci 986:625-7 |
| McDonough, Alicia A; Thompson, Curtis B; Youn, Jang H (2002) Skeletal muscle regulates extracellular potassium. Am J Physiol Renal Physiol 282:F967-74 |
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