Involvement of TREK-1 Activity in Astrocyte Function and Neuroprotection Under Simulated Ischemia Conditions

Abstract

Astrocytes play a fundamental role in the pathogenesis of ischemic neuronal death. The optimal operation of electrogenic astrocytic transporters and exchangers for some well-defined astrocyte brain homeostatic functions depends on the presence of K(+) channels in the cell membranes and the hyperpolarized membrane potential. Our previous study showed that astrocytes functionally express two-pore domain K(+) channel TREK-1, which helps to set the negative resting membrane potential. However, the roles of TREK-1 on astrocytic function under normal and ischemic conditions remain unclear. In this study, we investigated the expression of TREK-1 protein on cultured astrocytes and the effect of TREK-1 activity on astrocytic glutamate clearance capacity and release of s100β after simulated ischemic insult. TREK-1 immunoreactivity was up-regulated after hypoxia. Suppression of TREK-1 activity inhibited the glutamate clearance capability, enhanced the inflammatory secretion of astrocytes derived s100β and led to increased neuronal apoptosis after ischemic insult. Our results suggest that TREK-1 activity is involved in astrocytic function and neuronal survival. This would provide evidence showing astrocytic TREK-1 involvement in ischemia pathology which may serve as a potential therapeutic target in stroke.

Increased expression of hyperpolarization‐activated cyclic nucleotide‐gated (HCN) channels in reactive astrocytes following ischemia

“…However, in brains 5W after ischemia we found many reactive astrocytes with significantly depolarized RMP and decreased R M . These altered properties suggest changes in the composition of cytoplasmic membrane channels, such as Kir4.1 or two-pore domain K 1 channels as shown previously (Kucheryavykh et al, 2009;Pivonkova et al, 2010;Wu et al, 2013). The recorded inward currents, sensitive to HCN channel blocker and co-agonist, together with the demonstrated Na 1 conductance, imply that the HCN channels are one of the main players in the altered membrane properties of reactive astrocytes.…”

Ischemia-induced cell depolarization: does the hyperpolarization-activated cation channel HCN2 affect the outcome after stroke in mice?

“…TREK1 protein expression was temporally increased in these cells at 6 h after hypoxia. However, blockade of TREK1 channels raised the number of hypoxia-induced neuronal apoptosis in a neuron-astrocyte co-culture indicating a neuroprotective role of TREK1 channels after hypoxia [41]. In line with that, former studies on K 2P channels in stroke also revealed that TASK1 and TREK1 are involved in neuroprotection after stroke in mice while a closely related channel (TASK3) had no influence.…”

Temperature Sensitivity of Two-Pore (K2P) Potassium Channels

“…Recent studies have suggested unexpected roles for TREK-1 in glutamate conductance (Hwang et al, 2014; Woo et al, 2012) and regulation of blood–brain barrier permeability (Bittner et al, 2013). Channel activity has been linked to several pathological conditions, such as cardiac hypertrophy (Wang et al, 2013), ischemia (Heurteaux et al, 2004; Laigle, Confort-Gouny, Le Fur, Cozzone, & Viola, 2012; Wu et al, 2013), and myocardial infarction (Zhao, Fu, Gao, Xie, & Cao, 2011). …”