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J. Gen. Physiol.,
Volume 111, Number 1, January 1, 1998 161-180
From the * Department of Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, Connecticut 06520;
and Functional coupling of Na+,K+-ATPase pump activity to a basolateral membrane (BLM) K+ conductance is crucial for sustaining transport in the proximal tubule. Apical sodium entry stimulates pump activity, lowering cytosolic [ATP], which in turn disinhibits ATP-sensitive K+ (KATP) channels. Opening of these KATP channels
mediates hyperpolarization of the BLM that facilitates Na+ reabsorption and K+ recycling required for continued
Na+,K+-ATPase pump turnover. Despite its physiological importance, little is known about the regulation of this
channel. The present study focuses on the regulation of the BLM KATP channel by second messengers and protein
kinases using membrane patches from dissociated, polarized Ambystoma proximal tubule cells. The channel is regulated by protein kinases A and C, but in opposing directions. The channel is activated by forskolin in cell-attached (c/a) patches, and by PKA in inside-out (i/o) membrane patches. However, phosphorylation by PKA is
not sufficient to prevent channel rundown. In contrast, the channel is inhibited by phorbol ester in c/a patches,
and PKC decreases channel activity (nPo) in i/o patches. The channel is pH sensitive, and lowering cytosolic pH
reduces nPo. Increasing intracellular [Ca2+] ([Ca2+]i) in c/a patches decreases nPo, and this effect is direct since [Ca2+]i inhibits nPo with a Ki of ~170 nM in i/o patches. Membrane stretch and hypotonic swelling do not significantly affect channel behavior, but the channel appears to be regulated by the actin cytoskeleton. Finally, the activity of this BLM KATP channel is coupled to transcellular transport. In c/a patches, maneuvers that inhibit turnover of the Na+,K+-ATPase pump reduce nPo, presumably due to a rise in intracellular [ATP], although the associated cell depolarization cannot be ruled out as the possible cause. Conversely, stimulation of transport (and thus
pump turnover) leads to increases in nPo, presumably due to a fall in intracellular [ATP]. These results show that the inwardly rectifying KATP channel in the BLM of the proximal tubule is a key element in the feedback system
that links cellular metabolism with transport activity. We conclude that coupling of this KATP channel to the activity
of the Na+,K+-ATPase pump is a mechanism by which steady state NaCl reabsorption in the proximal tubule may
be maintained.
Department of Medicine, University of Vermont, Burlington, Vermont 05401
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