Abstract
The activity of two pore domain potassium (K2P) channels regulates neuronal excitability and cell firing. Post-translational regulation of K2P channel trafficking to the membrane controls the number of functional channels at the neuronal membrane affecting the functional properties of neurons. In this review, we describe the general features of K channel trafficking from the endoplasmic reticulum (ER) to the plasma membrane via the Golgi apparatus then focus on established regulatory mechanisms for K2P channel trafficking. We describe the regulation of trafficking of TASK channels from the ER or their retention within the ER and consider the competing hypotheses for the roles of the chaperone proteins 14-3-3, COP1 and p11 in these processes and where these proteins bind to TASK channels. We also describe the localisation of TREK channels to particular regions of the neuronal membrane and the involvement of the TREK channel binding partners AKAP150 and Mtap2 in this localisation. We describe the roles of other K2P channel binding partners including Arf6, EFA6 and SUMO for TWIK1 channels and Vpu for TASK1 channels. Finally, we consider the potential importance of K2P channel trafficking in a number of disease states such as neuropathic pain and cancer and the protection of neurons from ischemic damage. We suggest that a better understanding of the mechanisms and regulations that underpin the trafficking of K2P channels to the plasma membrane and to localised regions therein may considerably enhance the probability of future therapeutic advances in these areas.
Highlights
Two pore domain potassium (K2P) channels encode background, or leak, K currents which are essential players in the regulation of the resting membrane potential and excitability of many mammalian neurons
The subfamilies vary in their amino acid sequence as well as in tissue distribution and pharmacology, but two characteristic features of all K2P channels are that they are not voltage-gated and they are not inhibited by the classical potassium channel blocking agents, TEA and 4-AP [44]
Another chaperone protein that has been implicated in the trafficking of TASK channels is p11, known as s100A10 or annexin II light chain. p11 is a member of the s100 family of E-F hand proteins and it is an adaptor protein that binds to annexin 2 and other substrates to play a role in endocytosis, membrane trafficking and actin polymerisation [66, 85]. p11 has been shown to target channels to specific microdomains in the plasma membrane and has been linked to the translocation of NaV1.8, ASIC and TRPV5/6 channels and the 5HT1b receptor [26, 84]
Summary
Two pore domain potassium (K2P) channels encode background, or leak, K currents which are essential players in the regulation of the resting membrane potential and excitability of many mammalian neurons. We will consider current evidence concerning the trafficking of K2P channels to the neuronal membrane and their localisation therein. There are two particular processes regarding K2P channel trafficking for which most evidence exists These are the regulation of trafficking of TASK channels from the endoplasmic reticulum (ER) or their retention within the ER [26, 56, 57, 64, 65, 95, 96] and the localisation of TREK channels to particular regions of the neuronal membrane [72, 73]. We begin with a brief, general summary of K channel trafficking; KV channel trafficking for which most evidence exists; to set out some important considerations, focus on the K2P channels themselves
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