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• TREK and TRESK contribute significantly to the pathophysiology of pain symptoms, migraine, and inflammatory diseases. • Interactions of TREK and TRESK might involve heterodimerization and compensatory regulation of their subunit expression. • Insights into this interplay might provide innovative therapeutic targets. TWIK-related spinal cord potassium (TRESK) and TWIK-related potassium (TREK) channels are both subfamilies of the two-pore domain potassium (K2P) channel group. Despite major structural, pharmacological, as well as biophysical differences, emerging data suggest that channels of these two subfamilies are functionally more closely related than previously assumed. Recent studies, for instance, indicate an assembling of TRESK and TREK subunits, leading to the formation of heterodimeric channels with different functional properties compared to homodimeric ones. Formation of tandems consisting of TRESK and TREK subunits might thus multiply the functional diversity of both TRESK and TREK activity. Based on the involvement of these channels in the pathophysiology of migraine, we here highlight the role as well as the impact of the interplay of TRESK and TREK subunits in the context of different disease settings. In this regard, we focus on their involvement in migraine and pain syndromes, as well as on their influence on (neuro-)inflammatory processes. Furthermore, we describe the potential implications for innovative therapeutic strategies that take advantage of TRESK and TREK modulation as well as obstacles encountered in the development of therapies related to the aforementioned diseases. [ABSTRACT FROM AUTHOR]

Background: Cladribine is a synthetic purine analogue that interferes with DNA synthesis and repair next to disrupting cellular proliferation in actively dividing lymphocytes. The compound is approved for the treatment of multiple sclerosis (MS). Cladribine can cross the blood-brain barrier, suggesting a potential effect on central nervous system (CNS) resident cells. Here, we explored compartment-specific immunosuppressive as well as potential direct neuroprotective effects of oral cladribine treatment in experimental autoimmune encephalomyelitis (EAE) mice.Methods: In the current study, we compare immune cell frequencies and phenotypes in the periphery and CNS of EAE mice with distinct grey and white matter lesions (combined active and focal EAE) either orally treated with cladribine or vehicle, using flow cytometry. To evaluate potential direct neuroprotective effects, we assessed the integrity of the primary auditory cortex neuronal network by studying neuronal activity and spontaneous synaptic activity with electrophysiological techniques ex vivo.Results: Oral cladribine treatment significantly attenuated clinical deficits in EAE mice. Ex vivo flow cytometry showed that cladribine administration led to peripheral immune cell depletion in a compartment-specific manner and reduced immune cell infiltration into the CNS. Histological evaluations revealed no significant differences for inflammatory lesion load following cladribine treatment compared to vehicle control. Single cell electrophysiology in acute brain slices was performed and showed an impact of cladribine treatment on intrinsic cellular firing patterns and spontaneous synaptic transmission in neurons of the primary auditory cortex. Here, cladribine administration in vivo partially restored cortical neuronal network function, reducing action potential firing. Both, the effect on immune cells and neuronal activity were transient.Conclusions: Our results indicate that cladribine exerts a neuroprotective effect after crossing the blood-brain barrier independently of its peripheral immunosuppressant action. [ABSTRACT FROM AUTHOR]

K 2P 2.1 (TREK1), a two-pore domain potassium channel, has emerged as regulator of leukocyte transmigration into the central nervous system. In the context of skeletal muscle, immune cell infiltration constitutes the pathogenic hallmark of idiopathic inflammatory myopathies (IIMs). However, the underlying mechanisms remain to be elucidated. In this study, we investigated the role of K 2P 2.1 in the autoimmune response of IIMs. We detected K 2P 2.1 expression in primary skeletal muscle and endothelial cells of murine and human origin. We observed an increased pro-inflammatory cell response, adhesion and transmigration by pharmacological blockade or genetic deletion of K 2P 2.1 in vitro and in in vivo myositis mouse models. Of note, our findings were not restricted to endothelial cells as skeletal muscle cells with impaired K 2P 2.1 function also demonstrated a strong pro-inflammatory response. Conversely, these features were abrogated by activation of K 2P 2.1 and improved the disease course of a myositis mouse model. In humans, K 2P 2.1 expression was diminished in IIM patients compared to non-diseased controls arguing for the translatability of our findings. In summary, K 2P 2.1 may regulate the inflammatory response of skeletal muscle. Further research is required to understand whether K 2P 2.1 could serve as novel therapeutic target. • K 2P 2.1 (TREK1) is a potassium channel with immunoregulatory properties. • Immune cell infiltration is a pathophysiological hallmark of idiopathic inflammatory myopathies. • K 2P 2.1 regulates immune cell migration across the myovascular barrier, providing a potentially novel therapeutic target. [ABSTRACT FROM AUTHOR]