Functional interaction between K(ATP) channels and the Na(+)‐K(+) pump in metabolically inhibited heart cells of the guinea‐pig.

Abstract

1. Transmembrane current through ATP-regulated K+ channels (IK(ATP)) was measured in ventricular heart cells of the guinea-pig in the whole-cell and cell-attached patch configurations under conditions of metabolic poisoning with the mitochondrial uncoupler 2,4-dinitrophenol (DNP). 2. Maintained exposure of the cells to DNP resulted in a transient appearance of whole-cell IK(ATP). When IK(ATP) had reached several nanoamps, blocking the forward-running Na+-K+ pump with 0.5 mm strophanthidin decreased IK(ATP) after a delay. The time course of this decrease could be described by a single exponential function, which yielded a time constant (r) of 4-51 + 1P89 s (n = 8). 3. Hyperpolarization from 0 mV to -100 or -150 mV for 2 s caused IK(ATP) (measured at 0 mV) to decrease by 34-2 + 14 1 % (n = 8) and 37X6 + 9 4% (n = 8), respectively. After the hyperpolarizing pulse, IK(ATP) returned to its higher initial level within a couple of seconds. 4. Driving the pump backwards by removing the extracellular K+ ions caused the permanent disappearance of DNP-induced IK(ATP).5. Application of 0 5 mm strophanthidin in the absence of external K+ ions induced a transient increase in IK(ATP), as did washing out the glycoside (n = 5). 6. When pump action was inhibited by using Nae, K+-free Tyrode solution (see Methods) in the bath, strophanthidin did not have a comparable direct effect on IK(ATP)* 7. In cell-attached patches, strophanthidin applied via the bath caused a reduction in IK(ATP) with a similar time course to that in whole-cell experiments. This suggests that the interaction between the pump molecules and the KATP channels is not restricted to closely neighbouring molecules. 8. The data support the hypothesis that [ATP]

The Glycolytic Enzymes, Glyceraldehyde-3-phosphate Dehydrogenase, Triose-phosphate Isomerase, and Pyruvate Kinase Are Components of the KATP Channel Macromolecular Complex and Regulate Its Function

“…There is evidence to suggest that functional compartmentalization of ATP may be involved in receptor signaling, for example, the angiotensin II-mediated closure of cardiac K ATP channels (44). There is also a curious functional interaction between K ATP channels and the Na ϩ /K ϩ pump, whereby the activity of one determines the activity of the other, most likely by competition for the same glycolytically derived ATP (45)(46)(47)(48)(49). K ATP channels in vascular smooth muscle and glial cells have Kir6.1 as the pore forming subunit (1), which also interacts with GAPDH and PK.…”

Hyperpolarization of isolated capillaries from guinea‐pig heart induced by K+ channel openers and glucose deprivation

“…Our results are consistent with the hypothesis that local, submembrane ATP synthesis via glycolytic enzymes may be involved in the regulation of KATP channels in coronary capillaries. Thus, the glucosedependent regulation of membrane potential in coronary endothelium may be mediated by mechanisms similar to those found in cardiac muscle cells, where microcompartmentation of ATP synthesis has also been shown to influence the open-state probability of KATP channels (Weiss & Lamp, 1987;Priebe, Friedrich & Benndorf, 1996).…”

KATPChannels in the Cardiovascular System

“…This mode of regulation may become more pronounced with aging, since glycolytic inhibition in aged rat hearts causes action potential shortening and arrhythmias that can be prevented by K ATP channel block with glibenclamide (575). Competition for local glycolytically derived ATP may also be responsible for the known functional interaction between the K ATP channel and the Na ϩ /K ϩ pump, which has been observed in several tissues, including frog skin (829), neurons (8), the kidney (548), skeletal muscle (663), smooth muscle (269), and the heart (411,646). Although the physiological relevance of this functional interaction is obvious, it has been suggested to be important in the protective effects of ischemic preconditioning (IPC) (331).…”