The Trafficking of Nav1.8

Neuroscience Letters 486 (2010) 78–83

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Neuroscience Letters

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Review

The trafﬁcking of NaV1.8 Richard S. Swanwick, Alessandro Pristerá, Kenji Okuse ∗

Division of Cell & Molecular Biology, Imperial College London, London SW7 2AZ, UK article info abstract

Article history: The ␣-subunit of tetrodotoxin-resistant voltage-gated sodium channel NaV1.8 is selectively expressed in Received 25 June 2010 sensory neurons. It has been reported that NaV1.8 is involved in the transmission of nociceptive infor- Received in revised form 24 August 2010 mation from sensory neurons to the central nervous system in nociceptive [1] and neuropathic [24] pain Accepted 25 August 2010 conditions. Thus NaV1.8 has been a promising target to treat chronic pain. Here we discuss the recent advances in the study of trafficking mechanism of NaV1.8. These pieces of information are particularly Keywords: important as such trafficking machinery could be new targets for painkillers. Sodium Channel © 2010 Elsevier Ireland Ltd. Open access under CC BY license. Sensory Neuron Pain Trafficking

Contents

1. ER retention signals ...... 78 2. p11...... 79 3. PDZD2 ...... 79 4. Contactin ...... 79 5. PGE2-dependent trafﬁcking to the plasma membrane...... 81 6. CAP-1A ...... 81 7. Local translation ...... 82 References ...... 82

Membrane proteins are translated in the rough ER, post- 1. ER retention signals translationally modified and sorted during their migration through the Golgi to the plasma membrane. Interestingly, a large sub- The RXR motif, which serves as an ER retention signal, is found population of voltage-gated sodium channels are not directly in many membrane proteins, including ATP-sensitive potassium translocated to the plasma membrane, but stored in a metabolically channels [53],NMDA[40] and GABAB receptors [12].NaV1.8 pos- stable ‘intracelluar pool’ of folded protein [36]. This pool may per- sesses at least one functional ER retention signal within the first mit the neuron to respond rapidly to stimuli, allowing it to increase intracellular loop, consisting of residues RRR495–497 [54]. Substi- channel surface density faster than de novo synthesis would oth- tution of this motif with alanines results in an increased expression erwise allow. Recent reports describe many novel mechanisms of the channel on the membrane. The mechanism behind NaV1.8 which regulate the trafficking of ion channels to the plasma mem- release from the ER and trafficking to the cell surface has been brane occurring at many points along the pathway including the described. The auxiliary ␤3 subunit, which is expressed in dor- initial translation and folding, subsequent post-translational mod- sal root ganglia (DRG) neurons, associates with the ␣-subunit of ification e.g. N-glycosylation and palmitylation and by numerous voltage-gated sodium channels [48], and plays a key role in this pro- protein–protein interactions. cess. The intracellular C-terminus of the ␤3 subunit directly binds the portion of NaV1.8 containing the RRR signal [54] (Fig. 1). This interaction masks the retention signal and leads to the release of the channel from the ER. Other sodium channels also contain potential ER retention signals, although the position of this motif is not ∗ Corresponding author. conserved (e.g. NaV1.5 – RKR amino acid 480–482). Hence, simi- E-mail address: [email protected] (K. Okuse). lar mechanisms to control retention/trafficking to the membrane

channel subtypes also expressed in nociceptive neurons, such as NaV1.7 and NaV1.9 [33]. The identification of p11 as a chaperone protein for NaV1.8 has been followed by discoveries of many other membrane proteins controlled by p11 including TASK-1, 5-HT1B receptors, ASIC-1, TrpV5, and TrpV6. p11 promotes the membrane localisation of TASK-1 by masking an ER retention signal at the end of the C- terminal of the channel [13]. Interestingly p11 has also been reported to act as an ER retention factor by binding to the other region of the C-terminal of TASK-1 [35]. At present the ability of Fig. 1. Structure of the NaV1.8 showing the four homologous domains, each of which is composed of six membrane spanning segments. The S4 voltage sensors are shown p11 to act either ER retention factor or translocation promoter with in pink. The binding sites for the NaV1.8-interacting proteins are shown. The five sites different proteins is not understood. There is evidence to suggest for PKA phosphorylation at serine residues are indicated as “P”. that the carboxy terminus of p11 itself, may contain an ER retention motif, and thus interaction with other proteins may subsequently lead to ER retention [35]. Additionally, p11 could itself interact with could exist for the other sodium channel isoforms. It is known the other proteins masking their ER retention motifs, blocking their ␤3 subunit is up-regulated in small diameter neurons upon nerve effect and subsequently releasing the protein from the ER. axotomy [48], chronic constriction injury [41] and, in medium size neurons, in diabetic neuropathy models [42]. Thus, the ␤3 sub- 3. PDZD2 unit mediated NaV1.8 release from the ER could also account for increased excitability in pain states due to additional NaV1.8 being transported onto the cell membrane. PDZD2, also known as Papin, AIPC and PDZK3, is a large protein (2766 amino acid), which was identified as an interactor of NaV1.8 using the yeast two-hybrid system [30]. PDZD2 contains six PDZ 2. p11 domains, four located at the N-terminus and two at the C-terminus, and is thought to act as a scaffolding protein assisting the trafficking Although the ␤3 subunit has been shown to help translocation and/or clustering of target proteins [22]. PDZD2 is expressed in sev- of Na 1.8 from ER to the plasma membrane as described above, we V eral tissues including heart, lung, pancreas and DRG [52]. In DRGs, found that co-expression of accessory ␤-subunits did not help the PDZD2 is expressed in both small peripherin positive and large functional Na 1.8 expression in heterologous cells such as COS [3]. V NF200 positive neurons [44]. PDZD2 has been shown to directly This suggested that Na 1.8 requires other accessory proteins for V bind the second intracellular loop of Na 1.8 (between domain II its functional expression on the plasma membrane and led to the V and III) through its C-terminus (Fig. 1). Antisense mRNA and siRNA discovery of p11 as a novel permissive factor for Na 1.8 [32]. p11 V mediated knock-down of PDZD2 in DRG neurons in vitro leads to a (S100A10, Annexin 2 light chain) is a member of the S100 calcium drastic reduction of Na 1.8 mediated sodium currents [44] (Fig. 3). binding protein family, which regulates many cellular processes V Whether PDZD2 regulates the trafficking or the retention of Na 1.8 in response to intracellular calcium changes. p11 is expressed in V within the membrane has not yet been addressed. PDZD2 has also a large number of tissues and is present in many regions of the been shown to bind Na 1.7 and, may bind to all voltage-gated CNS including the cerebral cortex, hippocampus and hypothalamus V sodium channels via conserved PDZ binding motifs [44,45]. The [38,55]. It exists as a tight, non-covalent dimer and is the only mem- binding of PDZD2 to Na 1.8 and Na 1.7 (which together underlie ber of family to have suffered mutations within its EF hand motifs, V V action potential generation and propagation in unmyelinated noci- rendering it Ca2+ insensitive [19]. Although p11 cannot respond to ceptive fibres) suggests that PDZD2 may modulate cell excitability calcium fluctuations, it exists in a permanently “activated state” and ultimately pain thresholds. The role of PDZD2 in pain sensitivity compared to other members of the S100 family [18]. The major- has been investigated in PDZD2 knock-out mice, however no alter- ity of p11 present intracellularly, exists as a heterotetramer (A2t), ations in pain behaviours were observed (mechanical, thermal and composed of two identical annexin II heavy chains [19]. Annexin inflammatory pain models) [44]. The absence of a pain phenotype II, interacts in a Ca2+-dependent manner with negatively charged could be explained by the up-regulation of p11 that occurs in these phospholipids, also binding to cholesterol and many protein ligands mice, which could mask PDZD2 effects by increasing the amount including actin, and is thought to be involved in many membrane- of membrane associated Na 1.8 [44]. Interestingly, the assump- related events including endosome membrane trafficking along the V tion that Na 1.8 is solely expressed in DRG has been challenged recycling and degradation pathways [23,2]. The phosphorylation V by the discovery that both mouse and human atria and ventricles by PKC of Ser11 of Annexin II disrupts p11 binding [20], while the contain mRNA for Na 1.8 and significantly a mutation in the chan- activation of a protein phosphatase by PKA and subsequent dephos- V nel is linked to cardiac problems [6]. This mutation V1073A in the phorylation of the same residue [34] may allow coupling of the second intracellular loop of Na 1.8, is flanked by a putative phos- p11 localisation to the Ca2+ and cAMP-dependent cellular signalling V phorylation site (RKDS) and a class I PDZ binding motif. As both pathways. PDZD2 and syntrophin-associated serine/threonine kinase (SASTK) Both yeast two-hybrid and GST pull-down assays demonstrate have been shown to bind this intracellular loop [30] (Fig. 1), inter- that p11 binds to the amino terminus of Na 1.8, especially resides V action with these molecules may be linked to the trafficking and 74–103, located close to the start of the initial transmembrane electrophysiological properties of NaV1.8. domain [30] (Fig. 1). Upon co-expression of p11 with NaV1.8 in heterologous cells such as CHO, the channel successfully translocated to the plasma membrane [32] (Fig. 2), even in the absence 4. Contactin of additional ␤-subunits. In DRGs, in the absence of p11 (DRG specific knock-out), poor functional NaV1.8 expression is observed [9]. Contactin is a glycosyl-phosphatidylinositol-anchored CAM Interestingly, since functional expression is not totally abolished protein expressed by neurons. Reports show that it co- in the knock-out, additional factors expressed specifically by neu- immunoprecipitates with sodium channels from the brain and rons, may be capable of trafficking a small amount of the channel. enhances NaV1.2 currents when co-expressed with ␤1 subunit in a Significantly, p11 binds only to NaV1.8 and not to the other sodium heterologous system [21]. Also, the interaction between Contactin, 80 R.S. Swanwick et al. / Neuroscience Letters 486 (2010) 78–83

Fig. 2. (a) NaV1.8-like immunoreactivity in CHO-SNS22 cells. (b) Transient expression of GFP-p11 fusion protein in CHO-SNS22 cell. (c) Merged picture of (a) and (b) showing co-expression of p11 and NaV1.8 in the plasma membrane. (d and e) Microscopic images were quantitated using the NIH Image program. Densitometric measurements show the clear translocation of NaV1.8 into the plasma membrane in GFP-p11 transfected cells. Reproduced, with permission, from Ref. [32]. R.S. Swanwick et al. / Neuroscience Letters 486 (2010) 78–83 81

Fig. 3. (a) PDZD2 antisense mRNA expression in DRG neurons caused a loss of NaV1.8 current density. (b) Transfection of PDZD2-specific siRNA (conjugated to Alexa Fluor-488) into cultured DRG neurons caused efficient and specific down-regulation of endogenous PDZD2 protein expression. (c) The transfection of PDZD2 siRNA caused significant reduction of the NaV1.8 current density in DRG neurons. (d) Example TTX-resistant inward current traces from negative control siRNA and PDZD2 siRNA treated DRG neurons. Reproduced, with permission, from Ref. [44].

␤1 subunit, and Ankyrin is required to keep NaV1.2 at high den- EP4, which in turn activate intracellular Protein kinase A (PKA) sity on the cell membrane [28]. Further to this, Contactin binds (reviewed in Refs. [31,25]). PKA phosphorylates serine residues to NaV1.3, resulting in increased sodium peak currents without within the intracellular loop I of NaV1.8 and alters its gating prop- changing the electrophysiological properties of the channel [43].In erties, shifting its steady-state activation curve to a more negative addition, Contactin regulates NaV1.8 and NaV1.9 mediated currents potential [8] (Fig. 4). This change may account for an increase [37]. In Contactin knock-out mice, tetrodotoxin-resistant currents in NaV1.8 mediated sodium currents and higher cell excitability. are decreased while tetrodotoxin-sensitive currents are unaltered However, increased trafficking of NaV1.8 to the cell membrane in unmyelinated DRG neurons. In these animals the NaV1.8 activa- has recently been discovered to substantially contribute to this tion curve was shifted to a more depolarised potential (i.e. a greater phenomenon [27]. It has been demonstrated that PGE2 directly depolarisation is needed for activation) but no changes were appar- promotes surface expression of NaV1.8 in a dose-dependent man- ent for NaV1.9. Contactin deficient mice also exhibit a reduction of ner, and this effect can be blocked by cellular trafficking inhibitors. NaV1.8 and NaV1.9 (but not of NaV1.6 and NaV1.7) immunoreactiv- Forskolin, an activator of PKA, increases the NaV1.8 density on ity along unmyelinated axons in the sciatic nerve, suggesting a role the membrane and mutation of the phosphorylation sites (RXXS) of Contactin in regulating the surface expression of these channels. on NaV1.8 abolishes forskolin mediated effects. Interestingly, this effect of PKA phosphorylation is dependent on the ER retention 5. PGE2-dependent trafficking to the plasma membrane motif RRR (whose sequence is shared with a phosphorylation site), but is independent of the masking effect of the ␤3 subunit men- It is well established that during inflammatory conditions tioned above. several compounds such as prostaglandin E2 (PGE2), adenosine triphosphate, Bradykinin, nerve growth factor and histamine acti- 6. CAP-1A vate intracellular cascades resulting in sensitisation of nerve terminals and lowered pain thresholds. Among these compounds, Endocytosis is known to regulate the surface presentation of PGE2, a derivate of arachidonic acid, binds to its receptors, EP2 and many membrane proteins. Sodium channels have been demon- 82 R.S. Swanwick et al. / Neuroscience Letters 486 (2010) 78–83

Fig. 4. Comparison of voltage-dependence of current activation in wild-type NaV1.8 (WT) and the mutant NaV1.8 (SA) which lacks five PKA consensus phosphorylation sites within the intracellular loop between domain I and II. Representative currents and associated current–voltage plots from a wild-type NaV1.8-transfected cell and a cell transfected with mutant NaV1.8 (SA) are shown. The current–voltage plots shows decrease in peak current and right shift of voltage-dependence of activation in the mutant NaV1.8 expressed cells. Closed circle – NaV1.8 (WT); open circle – NaV1.8 (SA). Reproduced, with permission, from Ref. [8]. strated to be selectively degraded in acidic/lysosomal vesicles upon lation could contribute to increased axonal NaV1.8 protein levels. infection of DRG neurons by herpes simplex virus [47]. Using the Recent evidence using rapamycin inhibition of mTOR suggests that, C-terminus of NaV1.8 as bait in yeast two-hybrid screens, CAP-1A in DRG, A␦ but not C-fibre neurons contain the machinery to carry (Clathrin-associated protein-1A) was identified as a binding part- out local translation [17]. Interestingly, a small subset of C-fibres ner [26]. CAP-1A is thought to bind to a conserved motif also present may indeed be capable of local translation, although more work in other sodium channels such NaV1.2 [11] and act as an adaptor needs to be carried out to confirm this result. A recent study mea- protein, linking voltage-gated sodium channels to clathrin, which suring the axonal transport velocity of Kv1.2 recorded a rate of is involved in coated vesicle assembly. Calmodulin binding to an 0.8 ␮m/s [14]. Assuming this velocity is similar for sodium chan- IQ motif within the C-terminus has been proposed to disrupt CAP- nels, the transport of molecules to the extreme ends of the axon may 1A binding and subsequently inhibit its cell surface removal by the require many days. Plasma membrane inserted sodium channels endocytic pathway [7]. exhibit a half-life of around 50 h and those within the intracellular pool significantly less (∼30 h) [39]. These values place an upper 7. Local translation limit on the distance the channels could diffuse or be actively transported to their destination. There is a growing body of evidence suggesting that local trans- Because of its involvement in pain pathways and tissue-specific lation, where transcription is distal from the final location of localisation, NaV1.8 has been one of the best studied sodium chan- protein synthesis, is an important mechanism regulating many cel- nels and expected to be a good target for the treatment of chronic lular functions. mRNA transportation, localisation and subsequent pain. Although many attempts have been made to develop spe- “local translation” is thought to be especially important in highly cific blockers for NaV1.8 [10,16], the development of type-specific polarised cells, including neurons, where a rapid response to stim- blockers of individual sodium channels has remained challenging uli would be limited by long distance protein transport. In neuronal due to the similarities among the sodium channels. Successful use cells, it has been demonstrated to play a role in axonal growth of gabapentin/pregabalin for the treatment of neuropathic pain [29], long-term potentiation in the brain [5], synaptic plasticity [51] provided a new route to block channel activities, i.e. targeting and to modulate pain threshold [17]. At present, “local synthesis” accessory subunits to inhibit the localisation of calcium channels to of transmembrane proteins is controversial as their synthesis and the plasma membrane and/or to alter the activation kinetics [49]. post-translational modifications (e.g. glycosylation) requires both The trafficking mechanisms of NaV1.8 discussed above may provide ER and Golgi at the location of synthesis, although tantalising evi- such novel targets for the treatment of chronic pain. dence suggests that some membrane proteins can be synthesised locally such as GluR and IP3RI, where these membrane proteins are expressed along dendrites and at the synapses respectively [46,15]. 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