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Dominant negative effects of a non-conducting TREK1 splice variant expressed in brain.

Veale, Emma L., Rees, Kathryn A, Mathie, Alistair, Trapp, Stefan (2010) Dominant negative effects of a non-conducting TREK1 splice variant expressed in brain. The Journal of biological chemistry, 285 (38). pp. 29295-304. ISSN 1083-351X. (doi:doi: 10.1074/jbc.M110.10842) (KAR id:75886)

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Two-pore domain potassium (K(2P)) channels modulate neuronal excitability throughout the entire CNS. The stretch-activated channel TREK1 (K(2P)2.1) is expressed widely in brain and has been linked to depression, neuroprotection, pain perception, and epilepsy. Little, however, is known about the regulation of TREK1 expression on the transcriptional and translational level or about its trafficking to the plasma membrane. Here we have used PCR techniques to identify a splice variant of TREK1 expressed in the brain, which encodes a heavily truncated TREK1 protein retaining a single transmembrane domain. Functional expression of this splice variant TREK1ΔEx4 in tsA201 cells in the presence or absence of wild type TREK1 revealed that TREK1ΔEx4 has no channel activity itself but reduced TREK1 whole cell current amplitude. Confocal analysis of the expression of fluorescently tagged TREK1 variants revealed that TREK1ΔEx4 is translated, but it is retained in the intracellular compartment. Additionally, TREK1ΔEx4 reduced the level of TREK1 expression in the plasma membrane. Long and short forms of TREK1 derived from alternative translation initiation are differentially affected by TREK1ΔEx4, with the short form (lacking the first 41 amino acids at its N terminus) unaffected. This differential regulatory role of TREK1ΔEx4 will alter the functional profile of TREK1 current in neurons where they are expressed. These results indicate that the N-terminal domain and first transmembrane domain of TREK1 are likely to be important for channel dimerization and trafficking to the plasma membrane.

Item Type: Article
DOI/Identification number: doi: 10.1074/jbc.M110.10842
Uncontrolled keywords: Brain Fluorescence Gene Expression Ion Channels Potassium Channels Protein-Protein Interactions Trafficking K2P Channel KCNK Channel Splice Variant
Divisions: Divisions > Division of Natural Sciences > Medway School of Pharmacy
Depositing User: Emma Veale
Date Deposited: 19 Aug 2019 22:00 UTC
Last Modified: 16 Nov 2021 10:26 UTC
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