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Opening of K(ATP) channels is mandatory for acquisition of ischemic tolerance by adenosine
A Reshef1, O Sperling, E Zoref-Shani
1Department of Clinical Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, Israel.
Abstract:
Binding of adenosine to neuronal adenosine receptors activates a signal transduction pathway (the adenosine mechanism), leading to a temporary ischemic tolerance. We have demonstrated before that induction of this mechanism in primary rat neuronal cultures, by activation of adenosine receptors, or by activation of protein kinase C (PKC), confers a wide time window of ischemic tolerance, lasting up to 72h, the early (immediate) part of which depends on opening of K(ATP) channels (glibenclamide sensitive). Here we demonstrate that the entire duration of the ischemic tolerance conferred by activation of the adenosine mechanism depends on opening of the K(ATP) channels. Thus, opening of the K(ATP) channels appears to be a mandatory step in the adenosine mechanism, leading to the creation of the wide time window of ischemic tolerance.
Insights
Activating the adenosine mechanism in neurons confers ischemic tolerance by opening K(ATP) channels. This channel opening is essential for the entire duration of the protective effect, creating a wide time window of tolerance.
Area of Science:
- Neuroscience
- Cellular signaling
- Ischemic tolerance
Background:
- Adenosine receptors activate a signaling pathway (adenosine mechanism) inducing temporary ischemic tolerance.
- Previous studies showed this mechanism, activated by adenosine receptors or protein kinase C (PKC), confers up to 72h ischemic tolerance.
- The immediate phase of this tolerance depends on K(ATP) channel opening (glibenclamide sensitive).
Purpose of the Study:
- To investigate the role of K(ATP) channels in the entire duration of adenosine-mediated ischemic tolerance.
- To determine if K(ATP) channel opening is a mandatory step for sustained ischemic tolerance.
Main Methods:
- Primary rat neuronal cultures were used.
- Adenosine receptors and protein kinase C (PKC) were activated to induce the adenosine mechanism.
- The effect of glibenclamide (a K(ATP) channel blocker) on ischemic tolerance duration was assessed.
Main Results:
- The entire duration of ischemic tolerance induced by the adenosine mechanism was found to depend on K(ATP) channel opening.
- Blocking K(ATP) channels abolished the sustained ischemic tolerance conferred by adenosine receptor activation.
Conclusions:
- K(ATP) channel opening is a mandatory step in the adenosine mechanism.
- Opening of K(ATP) channels is crucial for establishing the wide time window of ischemic tolerance.
- The adenosine mechanism's protective effect against ischemia is critically dependent on sustained K(ATP) channel activity.