From the Background to the Spotlight: TASK Channels in Pathological Conditions

Abstract

TWIK-related acid-sensitive potassium channels (TASK1-3) belong to the family of two-pore domain (K(2P) ) potassium channels. Emerging knowledge about an involvement of TASK channels in cancer development, inflammation, ischemia and epilepsy puts the spotlight on a leading role of TASK channels under these conditions. TASK3 has been especially linked to cancer development. The pro-oncogenic potential of TASK3 could be shown in cell lines and in various tumor entities. Pathophysiological hallmarks in solid tumors (e.g. low pH and oxygen deprivation) regulate TASK3 channels. These conditions can also be found in (autoimmune) inflammation. Inhibition of TASK1,2,3 leads to a reduction of T cell effector function. It could be demonstrated that TASK1(-/-) mice are protected from experimental autoimmune inflammation while the same animals display increased infarct volumes after cerebral ischemia. Furthermore, TASK channels have both an anti-epileptic as well as a pro-epileptic potential. The relative contribution of these opposing influences depends on their cell type-specific expression and the conditions of the cellular environment. This indicates that TASK channels are per se neither protective nor detrimental but their functional impact depends on the "pathophysiological" scenario. Based on these findings TASK channels have evolved from "mere background" channels to key modulators in pathophysiological conditions.

The two-pore domain potassium channel KCNK5 deteriorates outcome in ischemic neurodegeneration

“…In principle, potassium channels can exert both anti-and pro-apoptotic effects [11,42]. Activation of potassium channels favors apoptosis in a broad array of cell types and pathophysiological scenarios (see Lang et al [42] for a comprehensive overview).…”

Enhancement of TWIK-related Acid-sensitive Potassium Channel 3 (TASK3) Two-pore Domain Potassium Channel Activity by Tumor Necrosis Factor α

“…They are responsible for native leak K currents found in many cell types including neurons such as cerebellar granule neurons (CGNs), where they underlie the background leak K current IK SO (5,6). TASK channels are known to play a role in various pathological conditions such as epilepsy, brain ischemia, cancer, and inflammation (7,8). TASK channels are regulated by anesthetics such as isoflurane and halothane that, by enhancing the K current, hyperpolarize neurons (9).…”

“…16). Because TASK3 channels regulate cellular potassium homeostasis, a role for these channels in other cellular processes such as oncogenesis and neuronal apoptosis has been proposed (7,17,18).…”

“…TASK3 channels have been shown to be of particular importance in cultured CGNs (17,18) and TASK1 and TASK3 channels in evoked inflammation (7,56,57). In CGNs, K loss through the native leak current IK SO (5,6), carried primarily by TASK3 channels (e.g.…”

Immunocytochemical Localization of TASK-3 Channels in Rat Motor Neurons

“…current in motor neurons cannot be explained by the known presence of the inwardly rectifying Kir2.2 and Kir2.4 channels (Karschin et al 1996;Töpert et al 1998;Prüss et al 2005). This current is strongly pH-sensitive, activated by inhalational anesthetics, and inhibited by Gq-coupled receptors, which is indicative of TASK currents Talley et al 2000); (4) TASK-like currents in motor neurons based on homodimeric or heterodimeric TASK-1 and TASK-3 complexes, regulate cellular excitability (Larkman and Perkins 2005) and contribute to immobilizing effects of anesthetics (Patel et al 1999;Sirois et al 2000;Lazarenko et al 2010); (5) TASK currents are strongly regulated by signals which are well known to participate in motor neuron excitability, such as Gq-alpha-protein coupled receptors for monoamines and other neurotransmitters Berg et al 2004;Perrier et al 2003); (6) TASK-3 channels were implicated in mitochondrial dysfunction, an important mechanism in ALS pathophysiology (Bittner et al 2010).…”