AMP-activated protein kinase connects cellular energy metabolism to KATP channel function

Abstract

AMPK is an important sensor of cellular energy levels. Objective The aim of these studies was to investigate whether cardiac KATP channels, which couple cellular energy metabolism to membrane excitability, are regulated by AMPK activity. Research Design and Methods We investigated effects of AMPK on rat ventricular KATP channels using electrophysiological and biochemical approaches Results Whole-cell KATP channel current was activated by metabolic inhibition; this occurred more rapidly in the presence of AICAR (an AMPK activator). AICAR had no effects on KATP channel activity recorded in the inside-out patch clamp configuration, but ZMP (the intracellular intermediate of AICAR) strongly activated KATP channels. An AMPK-mediated effect is demonstrated by the finding that ZMP had no effect on KATP channels in the presence of Compound C (an AMPK inhibitor). Recombinant AMPK activated Kir6.2/SUR2A channels in a manner that was dependent on the AMP concentration, whereas heat-inactivated AMPK was without effect. Using mass-spectrometry and co-immunoprecipitation approaches, we demonstrate that the AMPK α-subunit physically associates with KATP channel subunits. Conclusions Our data demonstrate that the cardiac KATP channel function is directly regulated by AMPK activation. During metabolic stress, a small change in cellular AMP that activates AMPK can be a potential trigger for KATP channel opening.

Energy-Dependent Modulation of Glucagon-Like Signaling inDrosophilavia the AMP-Activated Protein Kinase

“…There is evidence that AKH cells express the K + ATP channels based on in situ analysis and that dietary introduction of a specific K + ATP channel antagonist, tolbutamide (Henquin 1980), leads to behavioral phenotypes consistent with blocking AKH release (Kim and Rulifson 2004). AMPK has been shown to regulate the activation of this channel subtype (Yoshida et al 2012). Given the energy-sensing roles of K + ATP channel conductance, we are currently testing the contribution of this conductance in the regulation of AKH signaling and whether this intersects with AMPK signaling.…”

KATPChannels in the Cardiovascular System

“…Evolution has adapted to monitor changes in cellular energy status by responding to changes in AMP levels, for example, by activating AMP-activated protein kinase (AMPK), which has been described as the "fuel gauge of the mammalian cell" (326). Although AMP does not directly regulate K ATP channel opening (607), there is now evidence that AMP-dependent activation of AMPK increases ventricular K ATP channel open probability (905) and, similar to the situation in pancreatic ␤-cells (109, 632), enhances K ATP channel surface density through trafficking mechanisms (767,824). AMP may also participate in phosphotransfer reactions that are mediated by adenylate kinase to regulate the ADP/ATP ratio in the immediate vicinity of the channel to stimulate K ATP channel opening (100).…”

“…Other factors occurring during ischemia, such as cellular acidosis, changes in inorganic phosphate, adenosine production, and changes in phospholipid content may act to lower the channel=s ATP sensitivity and/or to promote its opening (124). For example, the K ATP channel is activated by AMPK (767,905), the guardian of cardiac energy status (325), and by adenylate kinase phosphotransfer reactions (100), as a result of small changes in intracellular AMP, which occurs rapidly. In dog heart, for example, the AMP/ ATP ratio doubles within just 1 min of regional ischemia, mainly due to an increase in the AMP levels (621).…”

“…A role for K ATP channels was demonstrated by the finding that Kir6.2 knockout reversed the cardioprotection elicited by AMPK activation (190). It appears that AMPK can affect K ATP channels in at least two ways: AMPK activation increases the open probability of ventricular K ATP channels (905), but also stimulates translocation of K ATP channels to the surface membrane; at least in pancreatic ␤-cells (109, 504, 632) (also see sect. VI).…”

AMP-Activated Protein Kinase

“…41 This observation raises the possibility that low-micromolar AMP concentrations, as seen in early ischemia and possibly intense exercise, open KATP channels by activating AMPK. This action could be an important contributor to cardioprotection but could also contribute to arrhythmogenesis by reducing APD and promoting reentry.…”