Abstract
Two-pore domain potassium (K2P) channels are implicated in an array of physiological and pathophysiological roles. As a result of their biophysical properties, these channels produce a background leak K+ current which has a direct effect on cellular membrane potential and activity. The regulation of potassium leak from cells through K2P channels is of critical importance to cell function, development and survival. Controlling the cell surface expression of these channels is one mode to regulate their function and is achieved through a balance between regulated channel delivery to and retrieval from the cell surface. Here, we explore the modes of retrieval of K2P channels from the plasma membrane and observe that K2P channels are endocytosed in both a clathrin-mediated and clathrin-independent manner. K2P channels use a variety of pathways and show altered internalisation and sorting in response to external cues. These pathways working in concert, equip the cell with a range of approaches to maintain steady state levels of channels and to respond rapidly should changes in channel density be required.
Similar content being viewed by others
Avoid common mistakes on your manuscript.
Introduction
Cellular endocytosis was classically viewed as a mechanism for protein internalisation and destruction. The identification of multiple endocytic pathways with defined cellular destinations helped recognise endocytosis as not only a means of reducing the expression of membrane proteins but also a mechanism to enable their rapid recycling and redistribution [13, 28, 78]. Endocytosis is now understood to be central to the fine control of cell surface expression and function of many membrane proteins.
Expression of two-pore domain potassium (K2P) channels on the cell surface is regulated at the transcriptional and post-transcriptional levels, via controlled biogenesis, sorting and trafficking [32, 65, 73]. These channels show constitutive activity once inserted into the plasma membrane and their surface expression directly impacts cell membrane potential by supporting K+ leak from cells [43, 65, 69]. Consequently, changes to channel surface density will result in changes in K+ leak, membrane depolarisation and hence, cellular function and excitation. Furthermore, as the 15 K2P family members show widespread tissue distribution and, as reviewed by others within this issue, are proposed to play roles in cellular mechanisms as diverse as chemoreception, adrenal development, cardiac function, pain, sleep and anaesthesia, the control of their surface density has the potential to impact an array of cellular physiological and pathophysiological processes [16, 46, 47, 90]. Our understanding of the mechanisms which regulate delivery of members of the K2P family to the cell surface has been elucidated over the last decade and is the focus of Renigunta et al. review (in this issue). Clearly, the recovery of K2P channels from the plasma membrane is of equal importance and a molecular understanding of the interplay between various endocytic pathways and environmental triggers is vital to our understanding of their roles in cell regulation. To date, we have limited knowledge of the pathways used by many of the K2P channels. This article will provide an overview of our current understanding of the predominant endocytic pathways utilised by ion channels and present recent evidence of endocytic pathway usage by members of the K2P family, including K2P1.1 (TWIK1), K2P2.1 (TREK1), K2P3.1 (TASK1) K2P9.1 (TASK3) and K2P18.1 (TRESK). Finally, using known criteria for recruitment of cargo into specific endocytic pathways, we speculate on likely modes of endocytosis of the remaining K2P family members.
Ion channel endocytosis
Cells use various mechanisms to internalise plasma membrane proteins (Fig. 1), and many proteins are capable of being recruited to different endocytic pathways in response to environmental triggers or as a result of constitutive or stimulated endocytosis [17, 20, 110]. The primary congregation point for most internalised proteins is the Rab5 (Ras-related GTPase 5) positive early endosome [11, 64, 114]. From here, proteins can either transit to recycling endosomes and back to the plasma membrane or are sorted to late endosomes and finally to the lysosome for degradation [11, 12, 93]. Similarly, at the trans-Golgi network (TGN), proteins can shuttle to the plasma membrane or be diverted to endosomes [12, 54]. An ARF6 (a member of the family of ADP-ribosylation factor) positive compartment operates as an alternative route to direct delivery of cargo to the Rab5 positive early endosomes [15, 59, 95, 96]. Proteins targeted to the ARF6 positive compartment can be recycled directly back to the cell surface or pass from there to early endosomes. On the whole, the endocytic routes and subsequent trafficking pathways (degradation versus recycling) are specified by structural features or sorting motifs within the cytoplasmic domains of cargo proteins [11, 114]. These endocytic signals enable binding partners to target the protein into specific pathways. While the molecular details of these processes are still emerging, recognised motifs and modifications have been defined.
Internalisation and intracellular sorting signals
The most extensively studied endocytic pathway is clathrin-mediated endocytosis (CME); however, a range of additional clathrin-independent endocytic pathways operate within different cell types and are proposed to account for a significant proportion of protein endocytosis [22, 28, 53, 75, 87]. Adaptor proteins (predominantly but not exclusively AP 1–4) together with clathrin-associated sorting proteins (CLASPs) recruit cargo into clathrin-coated vesicles of the CME pathway [62, 87, 92, 113]. Recruitment relies on recognition of sorting motifs predominantly within the cytosolic termini of cargo protein. A tyrosine motif (YXXϕ; using single amino acid code X represents a variable residue and ϕ a hydrophobic residue) and a di-leucine [DE]XXXL [LI] motif in channel c-termini are recognised by clathrin adaptor protein AP-2 (μ and α-δ2 subunits, respectively) [11]. AP-2 binding facilitates recruitment to the clathrin bud and results in channel endocytosis and lysosomal targeting. AP-1 and AP-3 also recognise these motifs but play roles in bidirectional transport between TGN and endosomes and sorting to lysosome (for AP-3 recruited cargo) [104, 109]. A similar motif, DXXLL or acidic cluster/di-leucine motif, is recognised by another member of the ARF family (ARF1) which is localised to the TGN and endosomes and regulates membrane recruitment of AP1 and AP3 [30, 81]. These motifs are thought not to be involved in cargo internalisation or recycling but likely enable sorting of transmembrane proteins from the TGN to endosomes.
Cargo bearing an alternative tyrosine motif ([FX]NPXY[FX]), as seen in Kir1.1, are also endocytosed through the CME pathway [11, 21, 35]. Here, recruitment into clathrin-coated vesicles appears to be independent of AP-2 but depends on CLASP proteins which either contain a phosphotyrosine-binding (PTB) domain and associate with either of PTB proteins, Disabled-2 (Dab2) and the autosomal recessive hypercholesterolemia (ARH) protein which localise to clathrin-coated structures [57, 79, 80]. [FX]NPXY[FX] motifs are also recognised by sorting nexin (SNX) proteins, endocytic proteins which contain phox-homology (PX) domains selective for endosomal phosphatidylinositol 3-phosphate (PtdIns(3)P) and function in cargo internalisation and endosomal sorting [19, 111, 116].
Clathrin-independent endocytosis
While CME is recognised by its distinctive cytoplasmic coat and well-defined mechanism for selection of cell surface cargo, evidence supports the existence of additional endocytic routes with less distinctive pathways and cargo recruitment. Together these pathways are grouped by their lack of dependence on a clathrin coat and machinery and are termed clathrin-independent endocytosis (CIE). As these pathways have less distinct coated vesicles and adaptor proteins, to date, few cargo motifs have been exclusively associated with a single CIE pathway [45, 70]. It is currently unclear how many CIE pathways exist and if incorporation into these pathways is via recruitment into vesicles or bulk release from plasma membrane [107]. Three general regulators of these pathways have been defined. CIE pathways are divided into those regulated by small GTPases ARF6, Cdc42/ARF1 and Rho A [29]. Most CIE pathways are dependent on actin and sensitive to plasma membrane cholesterol concentration [1, 45, 82, 107]. Cholesterol levels play an important regulatory role in the function of small GTPase Cdc42, as well as the recruitment of cholesterol interacting membrane proteins (e.g. flotillins) which enhance some CIE pathways [6, 42, 82]. While CIE is often described as a non-selective process, internal sorting of CIE cargo is evident. ARF6 activity regulates post-endocytic trafficking of CIE cargo [34]. By activating phosphatidylinositol 4-phosphate 5-kinase ARF6 can increase phosphatidylinositol 4,5 bisphosphate (PIP2). Inactivation of ARF6 following internalisation results in reduced PIP2 levels and supports the fusion of endocytic vesicles with early endosomes (containing CME cargo) [51, 55, 61]. ARF6 activation is also required for recycling of CIE cargo usually from the recycling tubular endosomes back to the plasma membrane through activation of phospholipase D [55, 101]. Indeed, ion channels containing acidic cluster (termed potassium acidic clusters or KAC) have been shown to be recruited into an ARF6-regulated recycling pathway [44]. Addition of KAC to cargo enables its rapid recycling to the plasma membrane via a route which bypasses the early endosome. ARF6, Rac, Ras or Sfc activation has also been implicated in plasma membrane ruffling and macropinocytosis [60, 97, 120].
Until recently, caveolae were believed to represent a distinct CIE pathway and were proposed to regulate ion channel function by controlling their trafficking [5, 91]. Recent data demonstrate that caveolae are static at the plasma membrane and caveosomes remain attached to the cell surface [39, 89]. These developments suggest that caveolae may function in organising ion channel macrodomains; however, they appear not to enable channel endocytosis [39].
While it remains unclear whether cargo is actively selected at the plasma membrane or is released from retention to enable internalisation via CIE, evidence suggests that endocytosis of CIE cargo may occur by different pathways under different cellular conditions [3, 110].
ARF6-dependent endocytosis is a key regulator of K2P1.1 (TWIK-1) surface expression
The wild-type protein of the first mammalian member of the K2P channel family, K2P1.1 (two-pore domain weak-inwardly rectifying potassium channel or TWIK) achieves low levels of functional expression [65–67, 83]. Various explanations for this low channel function have been proposed including channel inhibition by SUMOylation or more recently the identification of a hydrophobic gate within the channel inner cavity which disrupts K+ flux [4, 37, 98]. Channel removal from the cell surface will also negatively impact channel function and increasing evidence suggests that independently of biophysical properties of this channel; K2P1.1 shows low levels of surface expression with a high level of regulation of its expression on the cell surface. Wang et al. provide evidence of K2P1.1 expression within astrocytes but demonstrate that these channels are predominantly located within the cytoplasm [117]. In 2004, Decressac et al. examined subcellular localisation of K2P1.1 in both adult mouse kidney and Madin-Darby canine kidney (MDCK) cells stably expressing the channel [26]. K2P1.1 localised to a subapical cellular domain in the kidney and polarised MDCK cells, which was confirmed to be an apical recycling compartment by co-localisation with endobrevin (vesicle associate membrane protein or Vamp-8) a marker for recycling endosomes and the perinuclear and vesiculotubular compartments. In non-polarised cells, K2P1.1 localised to the equivalent perinuclear recycling compartment. A di-isoleucine motif in the c-terminus of K2P1.1 (I293,294) was demonstrated to be instrumental in channel internalisation. Mutation of I293 results in increased channel surface expression and current [36]. The motif either enhances delivery or enables internalisation of the channel. Evidence suggests that it is the latter, as pulse chase experiments show nascent wild-type channels with intact di-isoleucine motifs being delivered to the cell surface and then rapidly (<10 min) recycled to subapical compartment [36]. Channels with mutated motifs remained on the cell surface. Investigation into the nature of the motif found that it operates in a manner comparable to the di-leucine motif ([DE]XXXL[LI]) which enables cargo endocytosis via the CME with the potential to be recognised by AP-1, AP-2 or AP-3 [114]. Interestingly, Feliciangeli et al. demonstrate that endocytosis enabled by the di-isoleucine in the c-terminus of K2P1.1 is sensitive to the activity of the mechanochemical GTPase, dynamin, required for vesicle scission in CME [36]. However, a clear role for ARF6-dependent endocytosis is also reported [26]. Elegant experiments from the same group using active and inactive forms of the small G protein ARF6 demonstrate that ARF6 exchange factor EFA6 interacts with an overlapping region of K2P1.1 in an ARF6 dependent manner [26]. Dominant negative ARF6 was shown to promote surface expression of K2P1.1 [26, 59].
These findings suggest an interplay between the CME and CIE pathways with ARF6 enhancing CME [25, 61, 88]. D’Souza-Schorey et al. first reported this in 1995 when they observed that a constitutively active ARF6 mutant (ARF6Q67L) inhibited transferrin receptor internalisation while the inactive ARF6 (ARF6T27N) prevented its recycling to the plasma membrane [25]. A clear link between CME pathways and ARF6 is apparent. Indeed, an ARF6 GTPase activating protein (GAP), SMAP1, which converts ARF6 from GTP bound to an inactive GDP bound state, directly binds clathrin. Additionally ARF6-GTP has been proposed as a source of GTP for dynamin-dependent scission of clathrin buds [88]. Active ARF6 may also enable recruitment of AP2 to the plasma membrane due to its role in PIP2 production which could then recruit K2P1.1 to clathrin coated pits via it c-terminal di-isoleucine motif [51, 61].
The mode of interplay between the CME pathway and ARF6 for K2P1.1 sorting has yet to be fully ascertained; however, it is clear that K2P1.1 is internalised to a subapical compartment via di-isoleucine motif and is recycled in an ARF6-dependent manner, with the consequence of K2P1.1 being sequestered below the cell surface [26, 36]. This cellular strategy would explain the maintenance of a low level of this leak channel on the cell surface that could then be rapidly delivered to the plasma membrane or transported onto the endocytic pathway (early endosomes) in response to external cues. Indeed, activation of the serotonergic receptor results in increased K2P1.1 surface expression in the wild-type protein but not when the di-isoleucine motif has been disrupted [36]. 5-HT has previously been demonstrated to inhibit entorhinal cortex neurons in a K2P1.1-dependent manner [27]. These data provide insight into this mechanism and suggest that 5-HT triggers the release of K2P1.1 from the subapical recycling compartment increasing its cell surface expression and resulting in neuronal depolarisation. The molecular mechanisms of many aspects of these regulatory processes are still lacking significant detail but a clear role of endocytosis in the regulation of K2P1.1 is undeniable.
Does bulk endocytosis control surface expression of K2P18.1 (TRESK)?
An alternative strategy for neuronal cells to control the surface expression of potassium leak channels is proposed for K2P18.1 (also TWIK-related spinal cord potassium channel or TRESK). K2P18.1 exhibits predominantly neuronal expression and disruption of its function has been implicated in playing a role in migraine with aura [33, 63, 108]. TRESK contains a consensus site for the calcium-dependent phosphatase, calcineurin, within its large cytosolic loop between transmembrane domains 2 and 3 [24]. Calcineurin plays a role in activity-dependent bulk endocytosis (ADBE) in nerve termini [119]. While no direct experimental evidence has been provided for TRESK internalisation via ADBE in activated nerve termini, its recruitment to the complex and the indiscriminate nature of this endocytic pathway certainly supports the concept.
K2P2.1 binding partners impact channel plasma membrane density
Following K2P2.1’s (TWIK-related potassium channel 1 or TREK-1) molecular and biophysical characterisation, it rapidly became recognised as an important regulator of neuronal function [84]. K2P1.1 is implicated in depression, polymodal pain perception, diseases related to blood-brain barrier dysfunction and anaesthesia [2, 9, 38, 48, 52, 56]. Due to the neurological physiology and pathophysiology it impacts, modes of long-term regulation of K2P2.1 are particularly sought after. A-kinase anchoring protein (AKAP150), microtubule-associated protein (Mtap2) and neurotensin receptor 3 (NTSR3 also known as sortilin) have been identified as binding partners to K2P2.1 [76, 105, 106]. Both Mtap2 and NTSR3 are proposed to act by altering channel density. While Mtap2 interaction with K2P2.1 was shown to enhance channel density, it is unclear if this is due to enhanced delivery or reduced recovery at the plasma membrane [105]. NTSR3 promotes endocytosis and lysosomal sorting of neuronal cargo [18, 115, 118]. Interaction of a partial propeptide of NTSR3 (referred to as Spadin) with K2P2.1 resulted in 80 % of the complex being observed within the cell [76]. The researchers propose that activation of NTSR3 (through application of Spadin) results in endocytosis of both receptor and channel with likely targeting to TGN or lysosomes. To date, only protein interactions and channel density reduction have been confirmed experimentally and the precise pathways and channel destination have yet to be determined.
K2P3.1 utilises both CME and CIE pathways
K2P3.1 (TWIK-related acid sensitive potassium channel 1 or TASK-1) and K2P9.1 (TWIK-related acid sensitive potassium channel 3 or TASK-3) show a high degree of homology in sequence and biophysical properties with both channels sensitive to external pH and regulated by similar modulators [8, 31, 58, 99]. These channels have been proposed to function as heterodimers in some cells and indeed the forward transport of both channels appears to undergo similar regulation through post-translational modification and binding partner recruitment [23, 41, 71, 72, 85, 86, 100, 103, 121]. However, when considering K2P3.1 and K2P9.1 internalisation and subsequent sorting, these channels appear to diverge in their regulation. As the c-termini of these channels have a critical role in channel sorting and the c-termini of K2P3.1 and K2P9.1 show only 34 % homology, this divergence is not wholly unexpected.
Under unstimulated conditions, both K2P3.1 and K2P9.1 are internalised and appear within the early endosome within minutes of permitting endocytosis (through removal of temperature block) [71]. Quantification of the number of size-defined vesicles containing either of the internalised channels enabled comparison of the transit of both channels through the endocytic system. At specific time points, a higher number (>50 % increase) of endocytosed vesicles containing K2P9.1 compared to K2P3.1 were consistently observed [71]. This suggests that under unstimulated conditions either K2P9.1 is endocytosed more readily than K2P3.1 or indeed that it is retained within the endocytic pathway for longer (i.e. not shuttled back to the membrane or degraded). Both channels were found to colocalise with clathrin, and the number of endocytosed vesicles positive for both clathrin and either of the channels was dramatically reduced (∼50 % reduction) following disruption of the CME pathway by dynasore (a powerful dynamin GTPase inhibitor which prevents fission of clathrin buds) [40, 71, 74, 102]. Continued channel internalisation following inhibition of clathrin bud fission suggests the possibility of these channels also utilising an alternate or clathrin independent pathway for internalisation [71]. Fractionation experiments performed by Inoue et al. support this view as they observed the majority of K2P9.1 within a cell fraction in which transferrin receptor (a known cargo for CME) was also observed, but while K2P3.1 was also observed within this fraction, it was also observed in a fraction containing flotillin which is suggestive of CIE [74]. Endocytosed channels were observed in both the recycling (Rab 11 positive vesicles) and degradative (Lamp1 positive) pathways in a number of studies using cells with either endogenous or heterologous channel expression [40, 71, 74, 102].
Stimulated K2P3.1 internalisation has been demonstrated in a number of systems and is proposed to utilise specific motifs within the channel c-terminus. Nerve growth factor (NGF) activation of tyrosine kinase, TrKA, has been proposed to induce CME of K2P3.1 (but not K2P9.1) [74]. NGF treatment of either acutely isolated rat adrenal medulla cells which express K2P3.1 channels or a rat adrenal medulla cell line from a pheochromocytoma (PC12 cells) which express both K2P3.1 and K2P9.1 resulted in decreased functional expression of K2P3.1 and increased cytosolic expression of the channel [74]. Matsuoka et al. propose NGF stimulates K2P3.1 internalisation through CME. However, the possibility that some of the observed effects following NGF treatment (decreased functional expression and increased cytosolic localisation of the channel) are due to disruption of channel forward transport is not completely ruled out. A di-leucine motif (LL263/264) within K2P3.1 c-terminus has been implicated in recruiting the channel to clathrin pits, while two c-terminal potential tyrosine motifs (YAEM or YSIP; Y317 and Y340 in rat K2P3.1) were found not to contribute to the effect [74].
While Y317 was found not to be essential to NGF induced channel internalisation, a separate study found this motif to be critical to K2P3.1 endocytosis in the human ortholog. Reningunta et al. demonstrate a direct interaction between a member of the Q-SNARE family (Q-soluble N-ethylmaleimide-sensitive factor attachment protein receptor) syntaxin 8 (stx8) and K2P3.1 and utilising recombinant expression systems demonstrate that stx8 suppresses K2P3.1 current and surface expression [102]. This interaction was not observed with either stx7 (another member of the SNARE family) or K2P9.1. SNAREs operate by using a combination of various members of the Q and R-SNAREs to enable organelle-specific docking and fusion [50, 112]. Regulation of K2P3.1 surface expression by stx8 is lost by ablating a region of interaction on stx8 or by disrupting CME. Disruption of the Y317 (critical to YAEV motif in human K2P3.1 but absent from K2P9.1) disabled stx8-associated internalisation of K2P3.1 [102]. This work further demonstrated that both stx8 and K2P3.1 are endocytosed in a cooperative manner and within the same vesicles. An attractive hypothesis proposed by the authors is that cooperative recruitment of K2P3.1 and stx8 may influence their final destination through interaction with SNARE proteins localised to distinct subcellular compartments.
Protein kinase C (PKC) activation results in a decrease in K2P3.1 current and cell surface expression [7, 40]. Human embryonic kidney (HEK293T) cells heterologously expressing K2P3.1 or rat cerebellar granule neuron (CGN) with endogenous expression of the channel treated with phorbol myristate acetate (PMA), a potent activator of PKC resulted in K2P3.1 but not K2P9.1 internalisation and localisation within distinct intracellular puncta [40]. Similarly, activation of mGluR had a comparable effect with reduced current and increased K2P3.1 internalisation through CME. An REK motif analogous to a PKC-endocytosis motif identified and characterised in the dopamine transporter was found to be central to PKC-mediated endocytosis of K2P3.1 but lacking in K2P9.1 [40, 49, 68]. Gabriel et al. propose that this motif (SRERKLQYSIP) is similar to a mode II 14-3-3 binding motif and present evidence supporting the hypothesis that PKC-mediated endocytosis requires 14-3-3 [40]. The rationale for targeting 14-3-3β alone or the identification of the requisite phosphorylation site were lacking but intriguingly 14-3-3β knockdown had a negative impact on both channel cell surface expression and current following PKC activation. These findings present interesting avenues to explore in terms of the role played by 14-3-3 in balancing K2P3.1 forward transport and retrieval from the cell surface.
How much can signaling motifs tell us?
Endocytic signaling motifs are not conserved sequences but rather degenerate motifs in which two or three residues are critical for signal recognition. Recruitment to specific pathways is influenced by motif sequence; however, the ultimate fate of cargo following internalisation (degradation or recycling) is often determined not only by the pathway into which the protein is recruited but also by the affinity of adaptor proteins for variations within motif sequences [3, 110]. YXXϕ motifs, for example are recognised by AP proteins and are essential for the rapid internalisation of cargo from the plasma membrane [10, 114]. However, their function is not limited to endocytosis, since the same motif is implicated in the targeting of transmembrane proteins to lysosomes and lysosome-related organelles [10]. Evidence suggests that the variable residues (XXϕ) within the motif together with the phosphorylation state of the motif are central to recruiting specific AP isoforms and hence cargo destination. For example, YXXϕ signals involved in lysosomal targeting customarily have a Gly preceding the critical Tyr, while acidic X residues result in lysosomal sorting [10, 14, 114]. This scenario is made all the more complicated by many transmembrane proteins containing more than one motif (Table 1) and the functionality of the motif being influenced by its position within the channel cytosolic domain and flanking residues. The impact of post-translational modifications within the motif and surrounding residues (ubiquitination, palmitoylation, phosphorylation, glycosylation) have also been well documented to impact motif usage and cargo fate [17, 20, 77, 94]. When examining the K2P family of channels for prominent endocytic motifs, the majority of channels displayed an array of putative endocytic and sorting motifs (Table 1). Interestingly, none of the K2P channels contained the tyrosine motif [FX]NPXY[FX], previously identified in other ion channels [35]. Many K2P channels displayed multiple putative Yxxϕ motifs with up to four in some channels (Table 1). Many other membrane proteins contain a number of tyrosine motifs which on experimental analysis are not functionally relevant or may only be utilised under specific environmental conditions [17, 110]. Di-leucine or di-isoleucine motifs were only identified in K2P1.1 and K2P3.1 and both of these have been demonstrated to be functionally significant [36, 74]. Putative short proline-rich domains, which are proposed to enable sorting between endosomes and the TGN, were identified in five K2P channels, and for K2P15.1 (TASK-5) and K2P16.1 (TALK-1) these were the only putative endocytic sorting motifs identified (Table 1). While putative short acidic clusters (KAC) which are associated with protein retention within ARF6 positive recycling compartments were found in eight of the 14 human K2P channels examined [44]. As only a handful of the predicted motifs have been experimentally determined, and motif usage depends on both protein and cellular context, functional motifs and the fate of channels due to possession of a signal motif will need to be explored experimentally.
Even with our limited understanding of the endocytic processes utilised to regulate K2P channel functional expression, it is clear how versatile and important endocytosis could be in controlling the cell surface expression of such physiologically relevant proteins. As these channels enable K leakage from cells when they are expressed on the cell surface, their regulated removal from the plasma membrane and retention within recycling endosomes close to the cell surface appears a shrewd strategy to rapidly alter channel density in response to environmental stimuli. Equally, sorting these channels for destruction to regulate the optimal cell surface density either under unstimulated or stimulated conditions is a mode of regulation which if molecularly defined could have significant physiological and clinical implications.
References
Al-Awar O, Radhakrishna H, Powell NN, Donaldson JG (2000) Separation of membrane trafficking and actin remodeling functions of ARF6 with an effector domain mutant. Mol Cell Biol 20:5998–6007
Alloui A, Zimmermann K, Mamet J, Duprat F, Noel J, Chemin J, Guy N, Blondeau N, Voilley N, Rubat-Coudert C, Borsotto M, Romey G, Heurteaux C, Reeh P, Eschalier A, Lazdunski M (2006) TREK-1, a K+ channel involved in polymodal pain perception. EMBO J 25:2368–2376
Arjonen A, Alanko J, Veltel S, Ivaska J (2012) Distinct recycling of active and inactive beta1 integrins. Traffic 13:610–625
Aryal P, Abd-Wahab F, Bucci G, Sansom MS, Tucker SJ (2014) A hydrophobic barrier deep within the inner pore of the TWIK-1 K2P potassium channel. Nat Commun 5:4377
Balijepalli RC, Kamp TJ (2008) Caveolae, ion channels and cardiac arrhythmias. Prog Biophys Mol Biol 98:149–160
Balijepalli RC, Delisle BP, Balijepalli SY, Foell JD, Slind JK, Kamp TJ, January CT (2007) Kv11.1 (ERG1) K+ channels localize in cholesterol and sphingolipid enriched membranes and are modulated by membrane cholesterol. Channels (Austin) 1:263–272
Besana A, Barbuti A, Tateyama MA, Symes AJ, Robinson RB, Feinmark SJ (2004) Activation of protein kinase C epsilon inhibits the two-pore domain K+ channel, TASK-1, inducing repolarization abnormalities in cardiac ventricular myocytes. J Biol Chem 279:33154–33160
Bittner S, Budde T, Wiendl H, Meuth SG (2010) From the background to the spotlight: TASK channels in pathological conditions. Brain Pathol 20:999–1009
Bittner S, Ruck T, Fernandez-Orth J, Meuth SG (2014) TREK-king the blood-brain-barrier. J Neuroimmune Pharmacol 9:293–301
Bonifacino JS, Dell’Angelica EC (1999) Molecular bases for the recognition of tyrosine-based sorting signals. J Cell Biol 145:923–926
Bonifacino JS, Traub LM (2003) Signals for sorting of transmembrane proteins to endosomes and lysosomes. Annu Rev Biochem 72:395–447
Bonifacino JS, Rojas R (2006) Retrograde transport from endosomes to the trans-Golgi network. Nat Rev Mol Cell Biol 7:568–579
Bonifacino JS, Marks MS, Ohno H, Kirchhausen T (1996) Mechanisms of signal-mediated protein sorting in the endocytic and secretory pathways. Proc Assoc Am Physicians 108:285–295
Braulke T, Bonifacino JS (2009) Sorting of lysosomal proteins. Biochim Biophys Acta 1793:605–614
Brown FD, Rozelle AL, Yin HL, Balla T, Donaldson JG (2001) Phosphatidylinositol 4,5-bisphosphate and ARF6-regulated membrane traffic. J Cell Biol 154:1007–1017
Buckler KJ (2010) Two-pore domain k(+) channels and their role in chemoreception. Adv Exp Med Biol 661:15–30
Canto I, Trejo J (2013) Palmitoylation of protease-activated receptor-1 regulates adaptor protein complex-2 and -3 interaction with tyrosine-based motifs and endocytic sorting. J Biol Chem 288:15900–15912
Carlo AS, Nykjaer A, Willnow TE (2014) Sorting receptor sortilin-a culprit in cardiovascular and neurological diseases. J Mol Med (Berl) 92:905–911
Carlton J, Bujny M, Rutherford A, Cullen P (2005) Sorting nexins—unifying trends and new perspectives. Traffic 6:75–82
Chen B, Dores MR, Grimsey N, Canto I, Barker BL, Trejo J (2011) Adaptor protein complex-2 (AP-2) and epsin-1 mediate protease-activated receptor-1 internalization via phosphorylation- and ubiquitination-dependent sorting signals. J Biol Chem 286:40760–40770
Chen WJ, Goldstein JL, Brown MS (1990) NPXY, a sequence often found in cytoplasmic tails, is required for coated pit-mediated internalization of the low density lipoprotein receptor. J Biol Chem 265:3116–3123
Conner SD, Schmid SL (2003) Regulated portals of entry into the cell. Nature 422:37–44
Czirjak G, Enyedi P (2002) Formation of functional heterodimers between the TASK-1 and TASK-3 two-pore domain potassium channel subunits. J Biol Chem 277:5426–5432
Czirjak G, Toth ZE, Enyedi P (2004) The two-pore domain K+ channel, TRESK, is activated by the cytoplasmic calcium signal through calcineurin. J Biol Chem 279:18550–18558
D’Souza-Schorey C, Li G, Colombo MI, Stahl PD (1995) A regulatory role for ARF6 in receptor-mediated endocytosis. Science 267:1175–1178
Decressac S, Franco M, Bendahhou S, Warth R, Knauer S, Barhanin J, Lazdunski M, Lesage F (2004) ARF6-dependent interaction of the TWIK1 K+ channel with EFA6, a GDP/GTP exchange factor for ARF6. EMBO Rep 5:1171–1175
Deng PY, Poudel SK, Rojanathammanee L, Porter JE, Lei S (2007) Serotonin inhibits neuronal excitability by activating two-pore domain k+ channels in the entorhinal cortex. Mol Pharmacol 72:208–218
Doherty GJ, McMahon HT (2009) Mechanisms of endocytosis. Annu Rev Biochem 78:857–902
Donaldson JG, Porat-Shliom N, Cohen LA (2009) Clathrin-independent endocytosis: a unique platform for cell signaling and PM remodeling. Cell Signal 21:1–6
Doray B, Misra S, Qian Y, Brett TJ, Kornfeld S (2012) Do GGA adaptors bind internal DXXLL motifs? Traffic 13:1315–1325
Duprat F, Lesage F, Fink M, Reyes R, Heurteaux C, Lazdunski M (1997) TASK, a human background K+ channel to sense external pH variations near physiological pH. EMBO J 16:5464–5471
Enyedi P, Czirjak G (2010) Molecular background of leak K+ currents: two-pore domain potassium channels. Physiol Rev 90:559–605
Enyedi P, Braun G, Czirjak G (2012) TRESK: the lone ranger of two-pore domain potassium channels. Mol Cell Endocrinol 353:75–81
Eva R, Crisp S, Marland JR, Norman JC, Kanamarlapudi V, ffrench-Constant C, Fawcett JW (2012) ARF6 directs axon transport and traffic of integrins and regulates axon growth in adult DRG neurons. J Neurosci 32:10352–10364
Fang L, Garuti R, Kim BY, Wade JB, Welling PA (2009) The ARH adaptor protein regulates endocytosis of the ROMK potassium secretory channel in mouse kidney. J Clin Invest 119:3278–3289
Feliciangeli S, Tardy MP, Sandoz G, Chatelain FC, Warth R, Barhanin J, Bendahhou S, Lesage F (2010) Potassium channel silencing by constitutive endocytosis and intracellular sequestration. J Biol Chem 285:4798–4805
Feliciangeli S, Bendahhou S, Sandoz G, Gounon P, Reichold M, Warth R, Lazdunski M, Barhanin J, Lesage F (2007) Does sumoylation control K2P1/TWIK1 background K+ channels? Cell 130:563–569
Franks NP, Honore E (2004) The TREK K2P channels and their role in general anaesthesia and neuroprotection. Trends Pharmacol Sci 25:601–608
Furthauer M, Smythe E (2014) Systems dynamics in endocytosis. Traffic 15:338–346
Gabriel L, Lvov A, Orthodoxou D, Rittenhouse AR, Kobertz WR, Melikian HE (2012) The acid-sensitive, anesthetic-activated potassium leak channel, KCNK3, is regulated by 14-3-3beta-dependent, protein kinase C (PKC)-mediated endocytic trafficking. J Biol Chem 287:32354–32366
Girard C, Tinel N, Terrenoire C, Romey G, Lazdunski M, Borsotto M (2002) p11, an annexin II subunit, an auxiliary protein associated with the background K+ channel, TASK-1. EMBO J 21:4439–4448
Glebov OO, Bright NA, Nichols BJ (2006) Flotillin-1 defines a clathrin-independent endocytic pathway in mammalian cells. Nat Cell Biol 8:46–54
Goldstein SA, Bockenhauer D, O’Kelly I, Zilberberg N (2001) Potassium leak channels and the KCNK family of two-P-domain subunits. Nat Rev Neurosci 2:175–184
Gong Q, Weide M, Huntsman C, Xu Z, Jan LY, Ma D (2007) Identification and characterization of a new class of trafficking motifs for controlling clathrin-independent internalization and recycling. J Biol Chem 282:13087–13097
Gonnord P, Blouin CM, Lamaze C (2012) Membrane trafficking and signaling: two sides of the same coin. Semin Cell Dev Biol 23:154–164
Gurney A, Manoury B (2009) Two-pore potassium channels in the cardiovascular system. Eur Biophys J 38:305–318
Heitzmann D, Derand R, Jungbauer S, Bandulik S, Sterner C, Schweda F, El WA, Lalli E, Guy N, Mengual R, Reichold M, Tegtmeier I, Bendahhou S, Gomez-Sanchez CE, Aller MI, Wisden W, Weber A, Lesage F, Warth R, Barhanin J (2008) Invalidation of TASK1 potassium channels disrupts adrenal gland zonation and mineralocorticoid homeostasis. EMBO J 27:179–187
Heurteaux C, Lucas G, Guy N, El YM, Thummler S, Peng XD, Noble F, Blondeau N, Widmann C, Borsotto M, Gobbi G, Vaugeois JM, Debonnel G, Lazdunski M (2006) Deletion of the background potassium channel TREK-1 results in a depression-resistant phenotype. Nat Neurosci 9:1134–1141
Holton KL, Loder MK, Melikian HE (2005) Nonclassical, distinct endocytic signals dictate constitutive and PKC-regulated neurotransmitter transporter internalization. Nat Neurosci 8:881–888
Hong W (2005) SNAREs and traffic. Biochim Biophys Acta 1744:493–517
Honing S, Ricotta D, Krauss M, Spate K, Spolaore B, Motley A, Robinson M, Robinson C, Haucke V, Owen DJ (2005) Phosphatidylinositol-(4,5)-bisphosphate regulates sorting signal recognition by the clathrin-associated adaptor complex AP2. Mol Cell 18:519–531
Honore E (2007) The neuronal background K2P channels: focus on TREK1. Nat Rev Neurosci 8:251–261
Hsu VW, Prekeris R (2010) Transport at the recycling endosome. Curr Opin Cell Biol 22:528–534
Johannes L, Wunder C (2011) Retrograde transport: two (or more) roads diverged in an endosomal tree? Traffic 12:956–962
Jovanovic OA, Brown FD, Donaldson JG (2006) An effector domain mutant of ARF6 implicates phospholipase D in endosomal membrane recycling. Mol Biol Cell 17:327–335
Kennard LE, Chumbley JR, Ranatunga KM, Armstrong SJ, Veale EL, Mathie A (2005) Inhibition of the human two-pore domain potassium channel, TREK-1, by fluoxetine and its metabolite norfluoxetine. Br J Pharmacol 144:821–829
Keyel PA, Mishra SK, Roth R, Heuser JE, Watkins SC, Traub LM (2006) A single common portal for clathrin-mediated endocytosis of distinct cargo governed by cargo-selective adaptors. Mol Biol Cell 17:4300–4317
Kim Y, Bang H, Kim D (2000) TASK-3, a new member of the tandem pore K(+) channel family. J Biol Chem 275:9340–9347
Kobayashi H, Fukuda M (2013) ARF6, Rab11 and transferrin receptor define distinct populations of recycling endosomes. Commun Integr Biol 6:e25036
Koumakpayi IH, Le PC, Delvoye N, Saad F, Mes-Masson AM (2011) Macropinocytosis inhibitors and ARF6 regulate ErbB3 nuclear localization in prostate cancer cells. Mol Carcinog 50:901–912
Krauss M, Kinuta M, Wenk MR, De CP, Takei K, Haucke V (2003) ARF6 stimulates clathrin/AP-2 recruitment to synaptic membranes by activating phosphatidylinositol phosphate kinase type Iγ. J Cell Biol 162:113–124
Lafer EM (2002) Clathrin-protein interactions. Traffic 3:513–520
Lafreniere RG, Rouleau GA (2011) Migraine: role of the TRESK two-pore potassium channel. Int J Biochem Cell Biol 43:1533–1536
Lakadamyali M, Rust MJ, Zhuang X (2006) Ligands for clathrin-mediated endocytosis are differentially sorted into distinct populations of early endosomes. Cell 124:997–1009
Lesage F, Lazdunski M (2000) Molecular and functional properties of two-pore-domain potassium channels. Am J Physiol Renal Physiol 279:F793–F801
Lesage F, Guillemare E, Fink M, Duprat F, Lazdunski M, Romey G, Barhanin J (1996) TWIK-1, a ubiquitous human weakly inward rectifying K+ channel with a novel structure. EMBO J 15:1004–1011
Lesage F, Lauritzen I, Duprat F, Reyes R, Fink M, Heurteaux C, Lazdunski M (1997) The structure, function and distribution of the mouse TWIK-1 K+ channel. FEBS Lett 402:28–32
Loder MK, Melikian HE (2003) The dopamine transporter constitutively internalizes and recycles in a protein kinase C-regulated manner in stably transfected PC12 cell lines. J Biol Chem 278:22168–22174
Lotshaw DP (2007) Biophysical, pharmacological, and functional characteristics of cloned and native mammalian two-pore domain K+ channels. Cell Biochem Biophys 47:209–256
Maldonado-Baez L, Williamson C, Donaldson JG (2013) Clathrin-independent endocytosis: a cargo-centric view. Exp Cell Res 319:2759–2769
Mant A, Williams S, O’Kelly I (2013) Acid sensitive background potassium channels K2P3.1 and K2P9.1 undergo rapid dynamin-dependent endocytosis. Channels (Austin) 7:288–302
Mant A, Williams S, Roncoroni L, Lowry E, Johnson D, O’Kelly I (2013) N-glycosylation-dependent control of functional expression of background potassium channels K2P3.1 and K2P9.1. J Biol Chem 288:3251–3264
Mathie A, Rees KA, El Hachmane MF, Veale EL (2010) Trafficking of neuronal two pore domain potassium channels. Curr Neuropharmacol 8:276–286
Matsuoka H, Harada K, Nakamura J, Inoue M (2013) Nerve growth factor-induced endocytosis of TWIK-related acid-sensitive K(+) 1 channels in adrenal medullary cells and PC12 cells. Pflugers Arch 465:1051–1064
Mayor S, Pagano RE (2007) Pathways of clathrin-independent endocytosis. Nat Rev Mol Cell Biol 8:603–612
Mazella J, Petrault O, Lucas G, Deval E, Beraud-Dufour S, Gandin C, El-Yacoubi M, Widmann C, Guyon A, Chevet E, Taouji S, Conductier G, Corinus A, Coppola T, Gobbi G, Nahon JL, Heurteaux C, Borsotto M (2010) Spadin, a sortilin-derived peptide, targeting rodent TREK-1 channels: a new concept in the antidepressant drug design. PLoS Biol 8:e1000355
McCormick PJ, Dumaresq-Doiron K, Pluviose AS, Pichette V, Tosato G, Lefrancois S (2008) Palmitoylation controls recycling in lysosomal sorting and trafficking. Traffic 9:1984–1997
McMahon HT, Boucrot E (2011) Molecular mechanism and physiological functions of clathrin-mediated endocytosis. Nat Rev Mol Cell Biol 12:517–533
Mishra SK, Watkins SC, Traub LM (2002) The autosomal recessive hypercholesterolemia (ARH) protein interfaces directly with the clathrin-coat machinery. Proc Natl Acad Sci U S A 99:16099–16104
Mishra SK, Keyel PA, Hawryluk MJ, Agostinelli NR, Watkins SC, Traub LM (2002) Disabled-2 exhibits the properties of a cargo-selective endocytic clathrin adaptor. EMBO J 21:4915–4926
Nakai W, Kondo Y, Saitoh A, Naito T, Nakayama K, Shin HW (2013) ARF1 and ARF4 regulate recycling endosomal morphology and retrograde transport from endosomes to the Golgi apparatus. Mol Biol Cell 24:2570–2581
Nichols BJ, Lippincott-Schwartz J (2001) Endocytosis without clathrin coats. Trends Cell Biol 11:406–412
Nie X, Arrighi I, Kaissling B, Pfaff I, Mann J, Barhanin J, Vallon V (2005) Expression and insights on function of potassium channel TWIK-1 in mouse kidney. Pflugers Arch 451:479–488
Noel J, Sandoz G, Lesage F (2011) Molecular regulations governing TREK and TRAAK channel functions. Channels (Austin) 5:402–409
O’Kelly I, Goldstein SA (2008) Forward transport of K2P3.1: mediation by 14-3-3 and COPI, modulation by p11. Traffic 9:72–78
O’Kelly I, Butler MH, Zilberberg N, Goldstein SA (2002) Forward transport. 14-3-3 binding overcomes retention in endoplasmic reticulum by dibasic signals. Cell 111:577–588
Ohno H (2006) Clathrin-associated adaptor protein complexes. J Cell Sci 119:3719–3721
Palacios F, Schweitzer JK, Boshans RL, D’Souza-Schorey C (2002) ARF6-GTP recruits Nm23-H1 to facilitate dynamin-mediated endocytosis during adherens junctions disassembly. Nat Cell Biol 4:929–936
Parton RG, del Pozo MA (2013) Caveolae as plasma membrane sensors, protectors and organizers. Nat Rev Mol Cell Biol 14:98–112
Patel AJ, Honore E, Lesage F, Fink M, Romey G, Lazdunski M (1999) Inhalational anesthetics activate two-pore-domain background K+ channels. Nat Neurosci 2:422–426
Pelkmans L, Zerial M (2005) Kinase-regulated quantal assemblies and kiss-and-run recycling of caveolae. Nature 436:128–133
Perrais D, Merrifield CJ (2005) Dynamics of endocytic vesicle creation. Dev Cell 9:581–592
Platta HW, Stenmark H (2011) Endocytosis and signaling. Curr Opin Cell Biol 23:393–403
Ponimaskin E, Dumuis A, Gaven F, Barthet G, Heine M, Glebov K, Richter DW, Oppermann M (2005) Palmitoylation of the 5-hydroxytryptamine4a receptor regulates receptor phosphorylation, desensitization, and beta-arrestin-mediated endocytosis. Mol Pharmacol 67:1434–1443
Prigent M, Dubois T, Raposo G, Derrien V, Tenza D, Rosse C, Camonis J, Chavrier P (2003) ARF6 controls post-endocytic recycling through its downstream exocyst complex effector. J Cell Biol 163:1111–1121
Radhakrishna H, Donaldson JG (1997) ADP-ribosylation factor 6 regulates a novel plasma membrane recycling pathway. J Cell Biol 139:49–61
Radhakrishna H, Al-Awar O, Khachikian Z, Donaldson JG (1999) ARF6 requirement for Rac ruffling suggests a role for membrane trafficking in cortical actin rearrangements. J Cell Sci 112(Pt 6):855–866
Rajan S, Plant LD, Rabin ML, Butler MH, Goldstein SA (2005) Sumoylation silences the plasma membrane leak K+ channel K2P1. Cell 121:37–47
Rajan S, Wischmeyer E, Xin LG, Preisig-Muller R, Daut J, Karschin A, Derst C (2000) TASK-3, a novel tandem pore domain acid-sensitive K+ channel. an extracellular histiding as pH sensor. J Biol Chem 275:16650–16657
Rajan S, Preisig-Muller R, Wischmeyer E, Nehring R, Hanley PJ, Renigunta V, Musset B, Schlichthorl G, Derst C, Karschin A, Daut J (2002) Interaction with 14-3-3 proteins promotes functional expression of the potassium channels TASK-1 and TASK-3. J Physiol 545:13–26
Rankovic M, Jacob L, Rankovic V, Brandenburg LO, Schroder H, Hollt V, Koch T (2009) ADP-ribosylation factor 6 regulates mu-opioid receptor trafficking and signaling via activation of phospholipase D2. Cell Signal 21:1784–1793
Renigunta V, Fischer T, Zuzarte M, Kling S, Zou X, Siebert K, Limberg MM, Rinne S, Decher N, Schlichthorl G, Daut J (2014) Cooperative endocytosis of the endosomal SNARE protein syntaxin-8 and the potassium channel TASK-1. Mol Biol Cell 25:1877–1891
Renigunta V, Yuan H, Zuzarte M, Rinne S, Koch A, Wischmeyer E, Schlichthorl G, Gao Y, Karschin A, Jacob R, Schwappach B, Daut J, Preisig-Muller R (2006) The retention factor p11 confers an endoplasmic reticulum-localization signal to the potassium channel TASK-1. Traffic 7:168–181
Rous BA, Reaves BJ, Ihrke G, Briggs JA, Gray SR, Stephens DJ, Banting G, Luzio JP (2002) Role of adaptor complex AP-3 in targeting wild-type and mutated CD63 to lysosomes. Mol Biol Cell 13:1071–1082
Sandoz G, Tardy MP, Thummler S, Feliciangeli S, Lazdunski M, Lesage F (2008) Mtap2 is a constituent of the protein network that regulates twik-related K+ channel expression and trafficking. J Neurosci 28:8545–8552
Sandoz G, Thummler S, Duprat F, Feliciangeli S, Vinh J, Escoubas P, Guy N, Lazdunski M, Lesage F (2006) AKAP150, a switch to convert mechano-, pH- and arachidonic acid-sensitive TREK K(+) channels into open leak channels. EMBO J 25:5864–5872
Sandvig K, Torgersen ML, Raa HA, van Deurs DB (2008) Clathrin-independent endocytosis: from nonexisting to an extreme degree of complexity. Histochem Cell Biol 129:267–276
Sano Y, Inamura K, Miyake A, Mochizuki S, Kitada C, Yokoi H, Nozawa K, Okada H, Matsushime H, Furuichi K (2003) A novel two-pore domain K+ channel, TRESK, is localized in the spinal cord. J Biol Chem 278:27406–27412
Seaman MN (2008) Endosome protein sorting: motifs and machinery. Cell Mol Life Sci 65:2842–2858
Sigismund S, Argenzio E, Tosoni D, Cavallaro E, Polo S, Di Fiore PP (2008) Clathrin-mediated internalization is essential for sustained EGFR signaling but dispensable for degradation. Dev Cell 15:209–219
Teasdale RD, Collins BM (2012) Insights into the PX (phox-homology) domain and SNX (sorting nexin) protein families: structures, functions and roles in disease. Biochem J 441:39–59
Teng FY, Wang Y, Tang BL (2001) The syntaxins. Genome Biol 2:reviews3012-3012.7
Traub LM (2005) Common principles in clathrin-mediated sorting at the Golgi and the plasma membrane. Biochim Biophys Acta 1744:415–437
Traub LM, Bonifacino JS (2013) Cargo recognition in clathrin-mediated endocytosis. Cold Spring Harb Perspect Biol 5:a016790
Vaegter CB, Jansen P, Fjorback AW, Glerup S, Skeldal S, Kjolby M, Richner M, Erdmann B, Nyengaard JR, Tessarollo L, Lewin GR, Willnow TE, Chao MV, Nykjaer A (2011) Sortilin associates with Trk receptors to enhance anterograde transport and neurotrophin signaling. Nat Neurosci 14:54–61
van Vliet C, Thomas EC, Merino-Trigo A, Teasdale RD, Gleeson PA (2003) Intracellular sorting and transport of proteins. Prog Biophys Mol Biol 83:1–45
Wang W, Putra A, Schools GP, Ma B, Chen H, Kaczmarek LK, Barhanin J, Lesage F, Zhou M (2013) The contribution of TWIK-1 channels to astrocyte K(+) current is limited by retention in intracellular compartments. Front Cell Neurosci 7:246
Willnow TE, Petersen CM, Nykjaer A (2008) VPS10P-domain receptors - regulators of neuronal viability and function. Nat Rev Neurosci 9:899–909
Xue J, Graham ME, Novelle AE, Sue N, Gray N, McNiven MA, Smillie KJ, Cousin MA, Robinson PJ (2011) Calcineurin selectively docks with the dynamin Ixb splice variant to regulate activity-dependent bulk endocytosis. J Biol Chem 286:30295–30303
Zhang Q, Calafat J, Janssen H, Greenberg S (1999) ARF6 is required for growth factor- and rac-mediated membrane ruffling in macrophages at a stage distal to rac membrane targeting. Mol Cell Biol 19:8158–8168
Zuzarte M, Heusser K, Renigunta V, Schlichthorl G, Rinne S, Wischmeyer E, Daut J, Schwappach B, Preisig-Muller R (2009) Intracellular traffic of the K+ channels TASK-1 and TASK-3: role of N- and C-terminal sorting signals and interaction with 14-3-3 proteins. J Physiol 587:929–952
Acknowledgments
This work was supported by BBSRC grant BB/J008168/1 to IO. Thanks to the past and present members of the IO lab for contribution to knowledge.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
Open Access This article is distributed under the terms of the Creative Commons Attribution License which permits any use, distribution, and reproduction in any medium, provided the original author(s) and the source are credited.
About this article
Cite this article
O’Kelly, I. Endocytosis as a mode to regulate functional expression of two-pore domain potassium (K2P) channels. Pflugers Arch - Eur J Physiol 467, 1133–1142 (2015). https://doi.org/10.1007/s00424-014-1641-9
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00424-014-1641-9