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Role of the Na+-activated K+ channel Slack (Slo2.2) for cell survival upon ischemic stroke and myocardial infarction

Subject Area Pharmacology
Term from 2017 to 2024
Project identifier Deutsche Forschungsgemeinschaft (DFG) - Project number 354137032
 
Final Report Year 2024

Final Report Abstract

The Na+-activated K+ channel Slack (Slo2.2) is mainly expressed in neurons and cardiac myocytes. Slack is activated at high intracellular Na+ ([Na+]i) concentrations that are rarely reached under physiological conditions. Therefore, its function in cell physiology and pathophysiology is controversially discussed. Our recent findings imply that the massive increase in [Na+]i occurring under conditions of O2-deficiency (i.e. hypoxia or ischemia) can lead to the activation of Slack present in cardiac myocytes (CM). The outward Slack K+ currents presumably stabilize the membrane potential of the CM and thereby prevent an excessive influx of Ca2+, which is considered to be the central trigger of cell death when O2 is depleted. We were able to confirm these results in vivo in an established ischemia and reperfusion (I/R) injury model. We found that ischemia-induced myocardial damage was massively exacerbated in global and CM-specific conditional Slack mutants and that Slack function is essential for cardioprotection induced, for example, by mechanical conditioning maneuvers. We conclude that Slack could be a possible target for drugs in the prophylaxis and therapy of myocardial infarction. In a second project, we analyzed potential cell-protective functions of Slack in the neuronal system. Here, Slack-mediated hyperpolarization is considered a neuroprotective mechanism against excessive and repeated depolarization i.e. neuronal hyperactivity, induced, for example, by activating neurotransmitters such as glutamate or the glutamate analog Kainat (KA). Consistent with this notion, we found increased cell death in KA-exposed organotypic hippocampal slice cultures and dissociated hippocampal cultures in vitro after Slack ablation. Furthermore, KA-triggered Ca2+ influx and K+ efflux was increased in cultured Slack-deficient neurons compared to the corresponding Slack-proficient controls. These alterations in ion homeostasis could provide a plausible explanation for the altered action potential (AP) kinetics in Slack KO neurons, which ultimately results in a higher AP frequency in the presence of KA. In vivo, this led to an increased severity of acute KA-induced seizures in Slack KO. Based on the present data, we propose that Slack, as a gatekeeper of neuronal excitability, may be considered for acute limitation of the seizure severity of epilepsies. Taken together, our studies, which combine innovative cell and animal models in the cardiovascular system and in the CNS, show that Slack activity correlates with susceptibility to hypoxia/ischemia and excitotoxic processes, and thus influences cell survival.

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