TREK-1 in central nervous system diseases

To the Editor: The TWIK-related potassium channel (TREK-1), a member of the two-pore domain potassium (K2P) channel family, is critical in the pathophysiological processes of central nervous system (CNS) diseases. To date, researchers have extensively studied the role of TREK-1 in various neurological disorders. Notably, some studies suggest that activating TREK-1 may confer protective effects in conditions such as stroke, neuropathic pain, and epilepsy, whereas inhibiting TREK-1 may be more beneficial for treating depression and cognitive impairment. However, other studies present different views. Therefore, based on these conflicting roles of TREK-1 across different diseases, in this study, we aim to summarize the functions and mechanisms of TREK-1 in CNS disorders and offer insights that may inform future research directions. TREK-1, encoded by the KCNK2 gene, is one of the most extensively studied members of the K2P channel family. Its structure includes four transmembrane segments (M1–M4), two-pore domains (P1, P2), and an extended extracellular M1–P1 loop [Supplementary Figure 1, https://links.lww.com/CM9/C477].[1] These structural features offer potential targets for drug development, such as C3001a, which alleviates neuropathic pain by binding to a concealed site formed between the P1 and M4 of TREK-1. However, although several inhibitors and activators have been shown to modulate TREK-1 activity, their specific binding sites remain unidentified. Therefore, identifying distinct molecular binding sites will allow for more precise regulation of TREK-1 and serve as a valuable reference for developing targeted therapies. This could also help unravel the complexity of the role of TREK-1 in various conditions. TREK-1 exhibits a dual role in cerebral ischemia. Notably, some studies suggest that the activation of TREK-1 channels directly mediates the neuroprotective effects of polyunsaturated fatty acids (PUFAs) against global cerebral ischemia. Furthermore, volatile anesthetics that can activate TREK-1, such as sevoflurane and isoflurane, have also been shown to improve neurological function in animals following a stroke. However, the precise mechanisms underlying the neuroprotective effects of TREK-1 remain unclear. Current research indicates that this protection may be closely associated with astrocytes. First, TREK-1 expression has been detected in astrocytes, and its upregulation following ischemic insult, astrocytic activation, and proliferation has been observed.[2] Moreover, TREK-1 contributes to maintaining the passive conductance and membrane potential of astrocytes, a function that is associated with the presence of β-coat protein.[3] Notably, some studies indicate that inhibiting TREK-1 activity leads to decreased levels of glutamate transporter 1 in astrocytes, subsequently impairing glutamate clearance. Regarding the upstream regulatory mechanisms of TREK-1, astrocyte-elevated gene-1 (AEG-1) is currently considered a promising candidate.[4] This discussion explores the mechanisms through which TREK-1 exerts its neuroprotective effects in cerebral ischemia by modulating astrocytes [Supplementary Figure 2, https://links.lww.com/CM9/C477]. These findings provide preliminary insights into the role of TREK-1 in astrocytes, highlighting its potential as a therapeutic target for stroke. A considerable body of literature advocates for the neuroprotective role of TREK-1 in cerebral ischemia; however, it is pertinent to acknowledge conflicting reports suggesting that TREK-1 could potentially exacerbate brain injury. Three-(nitromethyl) isobenzofuran-1(3H)-one (lig4-4) selectively inhibits TREK-1 currents and exhibits neuroprotective effects against cerebral ischemia in the middle cerebral artery occlusion rat model. Additionally, the protective effects of S-(4-fluorobenzyl)-N-(3,4,5-trimethoxybenzoyl)-L-cysteinate (MTC) in rats with stroke are associated with the inhibition of excessive TREK-1 channel activation. Zheng et al argue that previous studies, which suggested the harmful effects of TREK-1 inhibition, merely elucidated its role in mediating the impact of preconditioning; however, whether TREK-1 itself possesses neuroprotective properties during ischemia remains unclear. Therefore, they directly observed changes in TREK-1 knockout mice after a stroke without any preconditioning and found that TREK-1 knockout mice exhibited stronger neurological function than wild-type mice. Similarly, spadin, a targeted inhibitor of TREK-1, has been found to reduce the infarct area in mice following a stroke. However, mini-spadin, a truncated analog of spadin, activated TREK-1 channels at low doses. Therefore, administering this low dose of mini-spadin to post-stroke mice reduced their infarct area. This effect differs from that of spadin, further highlighting the complexity of the impact of TREK-1 on cerebral ischemia. Overall, there are two distinct viewpoints regarding the role of TREK-1 in cerebral ischemia [Supplementary Table 1, https://links.lww.com/CM9/C477]. What accounts for these contrasting perspectives? Our analysis reveals that studies supporting the neuroprotective role of TREK-1 activation primarily utilize PUFAs or volatile anesthetics, whereas those advocating the opposing viewpoint employ lig4-4, MTC, or spadin. From a target perspective, PUFAs and volatile anesthetics have broad targets. Therefore, in addition to affecting TREK-1 channels, they also exert various effects on metabolism, the immune, and cardiovascular systems. Consequently, the different activators or inhibitors used in the studies may be a major reason for the varying results. However, earlier studies focused on demonstrating the benefits of TREK-1 activation in cerebral ischemia, leading to a more detailed elucidation of the underlying molecular mechanisms. In contrast, the specific mechanisms through which TREK-1 knockout confers protection against cerebral ischemia remain unclear, representing a limitation of current research in this area. Therefore, future investigations on TREK-1 in cerebral ischemia would benefit from employing specific molecular targeted agents or gene knockout models to further clarify these mechanisms, thereby enhancing our understanding of the role of TREK-1. In contrast to the dual role of TREK-1 in stroke cases, the prevailing view regarding its role in depression is that inhibiting TREK-1 may provide protective effects [Supplementary Table 2, https://links.lww.com/CM9/C477]. Research has demonstrated that the antidepressant fluoxetine can inhibit TREK-1. Similarly, the drug sipatrigine, which also inhibits TREK-1, exhibits comparable antidepressant properties. Further experiments indicate that reducing TREK-1 channel activity in mice through pharmacological or gene knockout techniques can alleviate depressive symptoms. Two other studies have reported that activating the TREK-1 channel can relieve behaviors akin to depression; therefore, I believe the TREK-1 activators they employed were not specific to TREK-1, thus undermining the reliability of their conclusions due to interference from other ion channels. Therefore, the current consensus remains that inhibiting the TREK-1 channel may present a more effective therapeutic strategy, potentially surpassing the efficacy of fluoxetine. Notably, the pathogenesis of depression involves neurobiological mechanisms, neuroplasticity, and inflammatory processes. Currently, selective serotonin reuptake inhibitors (SSRIs) are among the most common antidepressants, acting primarily by enhancing the transmission of serotonin (5-HT). The 5-HT1A auto-receptors in the dorsal raphe nucleus (DRN) function through a negative feedback loop, activating TREK-1 channels and reducing neuronal excitability, thereby inhibiting the 5-HT signaling pathway. However, TREK-1 inhibitors diminish this response, increasing the average firing rate of 5-HT neurons in the DRN. Furthermore, TREK-1 inhibitors can enhance hippocampal cyclic-adenosine monophosphate (cAMP) response binding protein (CREB) phosphorylation through the protein kinase A (PKA)-phosphorylated CREB-brain-derived neurotrophic factor (BDNF) pathway, upregulating BDNF expression and promoting improvements in hippocampal neurogenesis and synaptic plasticity. Furthermore, inhibiting TREK-1 also mitigates the activation of A1 astrocytes in the hippocampus of depression models through the nuclear factor-kappa B pathway. These findings elucidate the mechanisms through which TREK-1 influences depression [Supplementary Figure 2, https://links.lww.com/CM9/C477] and highlight the significance of TREK-1 channels as potential targets for antidepressant therapies, offering valuable insights for novel treatment strategies. Neuropathic pain refers to pain caused by damage or disease affecting the somatosensory system. Studies have shown that TREK-1 activation can alleviate neuropathic pain, and the analgesic effect of morphine is also directly associated with the activation of TREK-1 channels. Conversely, the inhibition of TREK-1 channels exacerbates tactile hypersensitivity in rats. Mechanistically, the role of TREK-1 in these neuropathic pain models may be associated with phosphorylation regulation through PKA and protein kinase C. These findings suggest that the TREK-1 channel could be a potential target for pain relief. However, in the chronic constriction injury (CCI) model of neuropathic pain, researchers reported contrasting results, observing that inhibiting TREK-1 channels could alleviate CCI-induced neuropathic pain. This contradictory conclusion could be due to the different pain models used in the study or the use of the non-specific TREK-1 inhibitor MiR-183-5p [Supplementary Table 3, https://links.lww.com/CM9/C477]. This indicates that different models, methods, and inhibitors used in various studies may lead to different conclusions. Therefore, future research needs to further explore the mechanisms of TREK-1 channels in different neuropathic pain models and how to effectively target them to develop new therapeutic approaches. Epilepsy is a neurological disorder characterized by abnormal electrical activity in the brain, closely associated with cellular excitability. Potassium ion channels, such as TREK-1, are crucial in this process [Supplementary Table 4, https://links.lww.com/CM9/C477]. Studies have shown that caffeine and theophylline can inhibit TREK-1 through the cAMP/PKA pathway, leading to membrane depolarization, which may explain their pro-epileptic effects. Consistent with this, TREK-1 knockout mice display increased sensitivity to seizures. Additionally, researchers have found that enhancing TREK-1 expression can reduce the duration of status epilepticus. Furthermore, one study demonstrated that spadin did not exacerbate seizures in mice. The study used a low dose of spadin (100 µg/kg) to evaluate its safety in treating depression, and the results showed that this dose did not exacerbate seizures in mice. This may be due to the low dosage, similar to the clinical use of SSRIs: at low doses, the risk of seizures is minimal; however, the risk rises significantly as the dosage increases. Therefore, the mechanism through which SSRIs induce seizures may be associated with their inhibition of the TREK-1 channel. Cognitive impairment generally refers to abnormalities in cognitive functions such as thinking, memory, learning ability, or attention. In various cases of disease-related cognitive impairments, the literature suggests a dual role of the TREK-1 channel in cognitive function [Supplementary Table 5, https://links.lww.com/CM9/C477]. Studies have shown that knocking out TREK-1 can improve cognitive deficits induced by isoflurane in middle-aged mice and ameliorate social memory impairments in the Df(16)A+/− mouse model. In a post-stroke cognitive impairment model, researchers also found that sequential activation and inhibition of TREK-1 after stroke improved cognitive deficits in mice. One study conducted electrophysiological measurements on brain slices from TREK-1 knockout mice and found that the absence of TREK-1 enhanced postsynaptic α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor expression, thereby inhibiting the formation of long-term potentiation (LTP). The author compared this phenomenon to hippocampal cornu ammonis 1 (CA1) stimulation leading to synaptic saturation, which could induce seizures and impair memory, concluding that TREK-1 knockout mice experienced memory impairment. However, in my view, the explanation is not entirely convincing. The synaptic near-saturation caused by TREK-1 loss did not result in pathology but rather increased synaptic connectivity strength within physiological limits. Whitlock et al[5] also suggested that learning-induced synaptic enhancement could block high-frequency stimulation-induced LTP. Therefore, the electrophysiological phenomena observed in TREK-1 knockout mice may more accurately indicate enhanced synaptic connectivity. This enhancement could be better demonstrated under pathological conditions of cognitive impairment in mice. Additionally, some studies have reported that the memory of TREK-1 knockout mice is similar to that of wild-type mice. However, contrary to these findings, Li et al discovered that alpha-linolenic acid (ALA), a TREK-1 channel activator, improved learning and memory deficits in aged senescence-accelerated mice-prone eight mice. However, ALA is not a specific activator of TREK-1, and other studies have shown that ALA can improve cognition by modulating metabolism. Therefore, whether the activation of TREK-1 can enhance cognition remains unclear. Consequently, the role of TREK-1 in cognitive impairment requires further experimental validation; however, it also suggests that TREK-1 regulation could be critical for future therapies aimed at improving cognitive function. In conclusion, we find that perspectives on the role of TREK-1 vary across different diseases, and even within the same disease, TREK-1 exhibits a dual nature. Consequently, it is considered a relatively complex functional channel. Therefore, can TREK-1 be used for clinical diagnosis and treatment? Based on the current research progress, it seems too early to draw a definitive conclusion on this matter. Notably, some drugs have been shown to inhibit TREK-1; however, translational research on this channel remains limited, with current studies primarily focused on exploring and developing targeted inhibitors. Therefore, clarifying the precise role of TREK-1 in various diseases through these targeted inhibitors should be prioritized and serve as a foundation for clinical translational research. However, the broad association of TREK-1 with multiple brain disorders and the inconsistent effects it exhibits may significantly limit its potential in drug development and translational studies. Consequently, considering that some clinical drugs also inhibit TREK-1 without causing severe side effects in patients, the clinical translation of TREK-1 is not entirely unattainable. Therefore, more in-depth research is required to provide further evidence supporting its potential therapeutic role in disease treatment. Funding This work was supported by grants from the National Natural Science Fund of China (Nos. 82171465 and 82001272). Conflicts of interest None.