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TWIK-related potassium channels (TREK) belong to a subfamily of the two-pore domain potassium channels family with three members,TREK1,TREK2 and TWIK-related arachidonic acid-activated potassium channels.The two-pore domain potassium channels is the last big family of channels being discovered,therefore it is not surprising that most of the information we know about TREK channels predominantly comes from the study ofheterologously expressed channels.Notwithstanding,in this review we pay special attention to the limited amount of information available on native TREK-like channels and real neurons in relation to neuroprotection.Mainly we focus on the role of free fatty acids,lysophospholipids and other neuroprotective agents like riluzole in the modulation of TREK channels,emphasizing on how important this modulation may be for the development of new therapies against neuropathic pain,depression,schizophrenia,epilepsy,ischemia and cardiac complications.