Project Details
Projekt
Molecular physiology and pharmacology of TRESK K2P K+ channels
Subject Area
Anatomy and Physiology
Term
since 2022
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 506373940
The TRESK potassium ion channel belongs to the multifaceted Two-Pore-Domain Potassium (K2P) channel family, important regulators of cellular excitability, which participate in many physiological and pathophysiological processes from hormone secretion and chemosensation to anaesthesia, neuroprotection and pain. TRESK channels are highly expressed in dorsal root ganglia as well as trigeminal ganglia neurons and involved in pain sensation such as migraine constituting promising pharmacological targets. TRESK currents are strongly regulated by (de)phosphorylation via Calcineurin and several Phosphokinases (e.g. MAPK, PKA and PKC) that target a large cytoplasmic domain unique to the TRESK channel. Furthermore, important cellular lipids including DAG, arachidonic acid, anandamide and 2-AG were found to inhibit TRESK activity but its physiological relevance is unexplored. In addition, many small drug molecules inhibit this channel by a poorly understood mechanism. Finally, TRESK channels have been recently shown to form heteromers with TREK-1 and TREK-2 and these heteromers are involved in certain conditions of migraine. Thus, despite its promising implication in the treatment of pain conditions, the channel is still poorly characterized and TRESK function is not understood mechanistically. Here we propose to apply systematic scanning mutagenesis, cysteine modification, homology modeling and patch-clamp electrophysiology to (1) identify the small molecule and lipid binding sites, (2) gain insight into the nature of the intrinsic TRESK gate regulated by e.g. phosphorylation, and (3) explore the receptor pathways that affect TRESK channels via the release of lipid messengers and (4) characterize TREK/TRESK heteromers with respect to the knowledge gathered here on homomeric TRESK channels. This project therefore aims to promote mechanistic insight into the poorly understood molecular physiology and pharmacology of TRESK channels.
DFG Programme
Research Grants
