Potassium Channels

Kidney International (1995) 48, 1017–1023; doi:10.1038/ki.1995.384

Cross-talk and the role of KATP channels in the proximal tubule

Paul A Welling

Department of Physiology, University of Maryland School of Medicine, Baltimore, Maryland, USA

Correspondence: Paul A Welling MD, Department of Physiology, University of Maryland School of Medicine, Baltimore, Maryland 21201, USA.

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Abstract

Faithfully shuttling scores of different solutes between various bodily compartments, epithelia are strategically equipped with a plethora of diverse ion channels, cotransporters, exchangers and active pumps. Despite their functional eccentricities, however, these transport molecules don't toil away as renegade individualists. Rather, by continuously talking to their transporting companions through multiple and overlapping signaling pathways [1, 2], they consort to preserve intracellular homeostasis in the face of physiologic alterations in transcellular solute transport.

The renal proximal tubule is no exception to the cross-talk phenomena. While recapturing the bulk of the glomerular ultra-filtrate, the proximal tubule amazingly reabsorbs about ten times its own weight in intracellular Na about once every minute [3, 4]. The cellular volume and intracellular potassium content are turned over at similar pace. Obviously, under the pressure of these herculean transcellular transport rates, intracellular homeostasis is constantly threatened. Even small physiological alterations in the filtered solute load and subsequent changes in transport through the cell would have dramatic and deleterious consequences on the intracellular milieu if it wasn't for the cross-talk signaling pathways that balance the activities of transporters carrying solutes into the cell with those that affect solute exit.

For instance, consider the homeostatic conversation between the Na,K-ATPase and the potassium conductive pathway on the basolateral membrane [2, 5–13] observed during a substrate-evoked boost in transcellular Na reabsorption (Fig. 1). In the proximal tubule and other leaky epithelial, like the small intestine [3, 4, 14–16], the vectorial transport of Na from lumen to blood is governed by the in-series operation of a number of different, Na-coupled solute carriers at the apical membrane and an active Na-translocation step, the Na,K-ATPase, on the basolateral membrane. By design, the passage of Na into the cell is dependent on the availability of its cotransported partners [4, 14–18]. Subsequently, when substrates like glucose or amino acids are added to the lumenal compartment, apical Na entry is turned on [14, 17, 19]. Transcellular sodium reabsorption then accelerates as the active efflux step across the basolateral membrane, the Na,K-ATPase, increases to match passive Na entry by mechanisms involving a Nai-dependent alteration in the turnover rate [16] and possibility an increase in functional pump number or change in kinetic properties [20]. Remembering, that the Na,K-ATPase actively translocates three sodium ions in exchange for two potassium ions per cycle [21], first principals predict that the increase in pump rate would occur at the expense of a harmful elevation of intracellular K and cell volume. Neither happens. Instead, the basolateral K conductive pathway, comprised of K-selective channels [reviewed in 22, 23], is summoned to augment its activity in parallel with the increase in Na,K-ATPase turnover. The synchronized cross-talk response insures that the obligate active influx of potassium through the Na,K-ATPase will be efficiently recycled back across the basolateral membrane. In this way, intracellular K activity [7, 12], cell volume [5] and membrane potential [11, 24] are preserved during physiological surges in electrogenic Na transport. An analogous response reduces the extent passive K efflux and prevents deleterious K dumping when the activity of the Na,K-ATPase is reduced [15, 25, 26].

Although the tight and parallel coupling between the activity of the Na,K-ATPase and the magnitude of the K conductance at the basolateral membrane is a fundamental and essential property of nearly all salt translocating epithelial [2], the underlying transduction mechanism had proved to be rather elusive. Only in the last few years, with the application of the patch-clamp technique and the ability to mointor intracellular levels of potential coupling modulators, have the pieces of the pump-leak coupling puzzle begun to fit together. The role variety of putative signaling modulators, such as membrane stretch [6, 27–29], changes in Ca [10, 30] and pHi [11, 31 32] have now been clarified. Several laboratories have conclusively implicated the role of ATP-sensitive K channels and changes in intracellular ATP levels [13, 25, 26]. The present review focuses on these recent developments and the role of KATP in the cellular physiology of the renal proximal tubule.

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