ATP-sensitive K+ channels in the kidney

Abstract

ATP-sensitive K+ channels (KATP channels) form a link between the metabolic state of the cell and the permeability of the cell membrane for K+ which, in turn, is a major determinant of cell membrane potential. KATP channels are found in many different cell types. Their regulation by ATP and other nucleotides and their modulation by other cellular factors such as pH and kinase activity varies widely and is fine-tuned for the function that these channels have to fulfill. In most excitable tissues they are closed and open when cell metabolism is impaired; thereby the cell is clamped in the resting state which saves ATP and helps to preserve the structural integrity of the cell. There are, however, notable exceptions from this rule; in pancreatic beta-cells, certain neurons and some vascular beds, these channels are open during the normal functioning of the cell. In the renal tubular system, KATP channels are found in the proximal tubule, the thick ascending limb of Henle's loop and the cortical collecting duct. Under physiological conditions, these channels have a high open probability and play an important role in the reabsorption of electrolytes and solutes as well as in K+ homeostasis. The physiological role of their nucleotide sensitivity is not entirely clear; one consequence is the coupling of channel activity to the activity of the Na-K-ATPase (pump-leak coupling), resulting in coordinated vectorial transport. In ischemia, however, the reduced ATP/ADP ratio would increase the open probability of the KATP channels independently from pump activity; this is particularly dangerous in the proximal tubule, where 60 to 70% of the glomerular ultrafiltrate is reabsorbed. The pharmacology of KATP channels is well developed including the sulphonylureas as standard blockers and the structurally heterogeneous family of channel openers. Blockers and openers, exemplified by glibenclamide and levcromakalim, show a wide spectrum of affinities towards the different types of KATP channels. Recent cloning efforts have solved the mystery about the structure of the channel: the KATP channels in the pancreatic beta-cell and in the principal cell of the renal cortical collecting duct are heteromultimers, composed of an inwardly rectifying K+ channel and sulphonylurea binding subunit(s) with unknown stoichiometry. The proteins making up the KATP channel in these two cell types are different (though homologous), explaining the physiological and pharmacological differences between these channel subtypes.

ATP-Sensitive Potassium Channels Modulate Glucose Transport in Cultured Human Skeletal Muscle Cells.

“…It is also known that KATP channel activity can be modulated by phosphorylation; in general, activation of protein kinase A has been found to be stimulatory, whereas protein kinase C is often inhibitory [15][16][17]. Thus, our findings that PMA-induced reversal of inhibition by PCO-400 of insulin-stimulated glucose uptake again support KATP channel involvement in this process.…”

Cloning of rabbit Kir6.1, SUR2A, and SUR2B: possible candidates for a renal KATP channel

“…The conductances range from 9 to 300 pS and the sensitivities to ATP and glibenclamide vary considerably: the IC 50 ranges from 10 M to 1 mM for ATP and from 3 nM to 250 M for glibenclamide (30,33,38). At the molecular level, reconstitution of ATP-sensitive K gests that Kir6.2/SUR1 could represent the pancreatic ␤-cell K ATP channel, Kir6.2/SUR2A or Kir6.2/SUR2B could be responsible, respectively, for the cardiac and smooth muscle K ATP channels, and Kir6.1/SUR2B could account for the vascular smooth muscle K ATP type (for review, see Ref.…”

Role of Potassium Channels in Regulation of Cerebral Vascular Tone

“…This characteristic may con fer sensitivity to glibenclamide in K+ channels that are not ATP-sensitive. Thus, the presence of glibenclamide sensitivity implicates a K+ channel but does not neces sarily indicate the presence of an ATP-sensitive K+ chan nel (Quast, 1996). In contrast to the calcium-activated and ATP-sensitive K+ channels, which are composed of protein complexes within the cell membrane, voltage dependent K+ channels consist of a pore-forming ex sub unit and a cytoplasmic regulatory f3 subunit (Rettig et aI., 1994).…”