Novel Roles of Plasma Membrane KATP Channels in the Heart

• Author / Creator

  Youssef, Nermeen Hosny Ibrahim

• Plasma membrane ATP-sensitive potassium (KATP) channels are found in many excitable cell types where they couple cellular metabolism and membrane excitability. . Studies on KATP deficient mice show that parameters of cardiac mechanical function are similar to those of wild-type mice under basal aerobic conditions. However, in the setting of ischemia-reperfusion injury hearts of mice lacking KATP channels were shown to recover poorly after the insult and exhibit larger infarct sizes than in wild-type mice. Absence of KATP channels was also shown to abolish the protective effects of ischemic and pharmacological preconditioning against ischemia-reperfusion injury. Recent evidence suggests that genetic ablation of the channel causes changes in global metabolism. Furthermore, a previous proteomic study has shown that genetic ablation of the KATP channels is associated with a noticeable change in cardiac metabolic proteins. In that regard, efficient energy utilization is one of the means by which the heart can recover functionally after ischemia. Therefore, if cardiac metabolism is suboptimal under basal aerobic conditions, it is likely that the heart becomes more susceptible to damage if subjected to an ischemic insult. In this thesis, the author investigates whether KATP channels regulate cardiac metabolism. If so, how would those changes in metabolic profile contribute to the pronounced cardiac damage observed during ischemia in KATP-deficient mice? In this regard, KATP channels were shown to possess Mg-ATPase activity in addition to their well-identified electrical activity. This Mg-ATPase activity allows the channel to alter the nucleotide concentration in its microenvironment which directly affects channel activity. Therefore, we sought to study the molecular determinants that regulate this enzymatic property. It is plausible that commonly used pharmacological agents that target KATP channels such as diazoxide and sulfonylureas may not only be affecting KATP electrical activity but Mg-ATPase activity as well. The functional consequences of these effects are unknown thus far, however, elucidation of these effects provides insight into the manifestation of side effects that may occur due to the use of such pharmacological agents. Due to the close association between KATP channels and several nucleotide-sensitive enzymes known to modulate metabolism, most notably AMP-activated protein kinase (AMPK), we investigated whether KATP channel openers and inhibitors affected activity of this enzyme. We also examined the effect of diazoxide, glibenclamide and gliclazide on Mg-ATPase activity of the channel in an effort to correlate the enzymatic activity of the channel and activity of AMPK. Overall, the findings in this thesis highlight the importance of the presence of an intact plasma membrane KATP channel metabolome in the regulation of cardiac metabolism via modulation of AMPK activity. Moreover, we show that alteration of Mg-ATPase activity can directly affect pharmacological sensitivity of KATP channels to drugs that are designed to modulate their electrical activity. Understanding the functional consequences of the alteration of non-electrical properties of KATP channels provides clues to aid the development of more specific pharmacological agents with less prominent adverse effects.

• Subjects / Keywords

  • KATP
  • heart
  • metabolism
  • channels
  • AMPK
  • sulfonylureas
  • diazoxide
  • cardiac function

• Graduation date

  Fall 2015

• Type of Item

  Thesis

• Degree

  Doctor of Philosophy

• DOI

  https://doi.org/10.7939/R37M0455J

• License

  This thesis is made available by the University of Alberta Libraries with permission of the copyright owner solely for non-commercial purposes. This thesis, or any portion thereof, may not otherwise be copied or reproduced without the written consent of the copyright owner, except to the extent permitted by Canadian copyright law.