Skip to main content
Open Access Publications from the University of California

Intracellular signalling mechanism responsible for modulation of sarcolemmal ATP-sensitive potassium channels by nitric oxide in ventricular cardiomyocytes

  • Author(s): Zhang, DM
  • Chai, Y
  • Erickson, JR
  • Brown, JH
  • Bers, DM
  • Lin, YF
  • et al.

Key points: Both the ATP-sensitive potassium (KATP) channel and the gaseous messenger nitric oxide (NO) play fundamental roles in protecting the heart from injuries related to ischaemia. NO has previously been suggested to modulate cardiac KATPchannels; however, the underlying mechanism remains largely unknown. In this study, by performing electrophysiological and biochemical assays, we demonstrate that NO potentiation of KATPchannel activity in ventricular cardiomyocytes is prevented by pharmacological inhibition of soluble guanylyl cyclase (sGC), cGMP-dependent protein kinase (PKG), Ca2+/calmodulin-dependent protein kinase II (CaMKII) and extracellular signal-regulated protein kinase 1/2 (ERK1/2), by removal of reactive oxygen species and by genetic disruption of CaMKIIδ. These results suggest that NO modulates cardiac KATPchannels via a novel cGMP-sGC-cGMP-PKG-ROS-ERK1/2-calmodulin-CaMKII (δ isoform in particular) signalling cascade. This novel intracellular signalling pathway may regulate the excitability of heart cells and provide protection against ischaemic or hypoxic injury, by opening the cardioprotective KATPchannels. The ATP-sensitive potassium (KATP) channels are crucial for stress adaptation in the heart. It has previously been suggested that the function of KATPchannels is modulated by nitric oxide (NO), a gaseous messenger known to be cytoprotective; however, the underlying mechanism remains poorly understood. Here we sought to delineate the intracellular signalling mechanism responsible for NO modulation of sarcolemmal KATP(sarcKATP) channels in ventricular cardiomyocytes. Cell-attached patch recordings were performed in transfected human embryonic kidney (HEK) 293 cells and ventricular cardiomyocytes freshly isolated from adult rabbits or genetically modified mice, in combination with pharmacological and biochemical approaches. Bath application of the NO donor NOC-18 increased the single-channel activity of Kir6.2/SUR2A (i.e. the principal ventricular-type KATP) channels in HEK293 cells, whereas the increase was abated by KT5823 [a selective cGMP-dependent protein kinase (PKG) inhibitor], mercaptopropionyl glycine [MPG; a reactive oxygen species (ROS) scavenger], catalase (an H2O2-degrading enzyme), myristoylated autocamtide-2 related inhibitory peptide (mAIP) selective for Ca2+/calmodulin-dependent protein kinase II (CaMKII) and U0126 [an extracellular signal-regulated protein kinase 1/2 (ERK1/2) inhibitor], respectively. The NO donors NOC-18 and N-(2-deoxy-α,β-d-glucopyranose-2-)-N2-acetyl-S-nitroso-d,l-penicillaminamide © 2013 The Physiological Society.

Many UC-authored scholarly publications are freely available on this site because of the UC Academic Senate's Open Access Policy. Let us know how this access is important for you.

Main Content
Current View