Neuroprotective role of ATP-sensitive potassium channels in cerebral ischemia
Abstract
Hong-shuo SUN1, 2, 3, 4, *, Zhong-ping FENG2, *
Departments of 1Surgery, 2Physiology, 3Pharmacology and 4Institute of Medical Science, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada M5S 1AB
ATP-sensitive potassium (KATP) channels are weak, inward rectifiers that couple metabolic status to cell membrane electrical activity, thus modulating many cellular functions. An increase in the ADP/ATP ratio opens KATP channels, leading to membrane hyperpolarization. KATP channels are ubiquitously expressed in neurons located in different regions of the brain, including the hippocampus and cortex. Brief hypoxia triggers membrane hyperpolarization in these central neurons. In vivo animal studies confirmed that knocking out the Kir6.2 subunit of the KATP channels increases ischemic infarction, and overexpression of the Kir6.2 subunit reduces neuronal injury from ischemic insults. These findings provide the basis for a practical strategy whereby activation of endogenous KATP channels reduces cellular damage resulting from cerebral ischemic stroke. KATP channel modulators may prove to be clinically useful as part of a combination therapy for stroke management in the future.
Keywords: ATP-sensitive potassium channel (KATP); Kir6.2; SUR subunit; stroke; nociception; neuropathic pain; neuroprotection
This work was supported by a Grant-In-Aid operating grant from the Heart and Stroke Foundation of Canada to HSS. ZPF holds a New Investigator Award from the Heart and Stroke Foundation of Canada.
* To whom correspondence should be addressed.
E-mail hss.sun@utoronto.ca (Hong-shuo SUN); zp.feng@utoronto.ca (Zhong-ping FENG)
Received 2012-04-19 Accepted 2012-08-26
Keywords:
Departments of 1Surgery, 2Physiology, 3Pharmacology and 4Institute of Medical Science, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada M5S 1AB
ATP-sensitive potassium (KATP) channels are weak, inward rectifiers that couple metabolic status to cell membrane electrical activity, thus modulating many cellular functions. An increase in the ADP/ATP ratio opens KATP channels, leading to membrane hyperpolarization. KATP channels are ubiquitously expressed in neurons located in different regions of the brain, including the hippocampus and cortex. Brief hypoxia triggers membrane hyperpolarization in these central neurons. In vivo animal studies confirmed that knocking out the Kir6.2 subunit of the KATP channels increases ischemic infarction, and overexpression of the Kir6.2 subunit reduces neuronal injury from ischemic insults. These findings provide the basis for a practical strategy whereby activation of endogenous KATP channels reduces cellular damage resulting from cerebral ischemic stroke. KATP channel modulators may prove to be clinically useful as part of a combination therapy for stroke management in the future.
Keywords: ATP-sensitive potassium channel (KATP); Kir6.2; SUR subunit; stroke; nociception; neuropathic pain; neuroprotection
This work was supported by a Grant-In-Aid operating grant from the Heart and Stroke Foundation of Canada to HSS. ZPF holds a New Investigator Award from the Heart and Stroke Foundation of Canada.
* To whom correspondence should be addressed.
E-mail hss.sun@utoronto.ca (Hong-shuo SUN); zp.feng@utoronto.ca (Zhong-ping FENG)
Received 2012-04-19 Accepted 2012-08-26