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The Trafficking of Nav1.8

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The Trafficking of Nav1.8 Neuroscience Letters 486 (2010) 78–83 Contents lists available at ScienceDirect Neuroscience Letters journal homepage: www.elsevier.com/locate/neulet 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 poten- tial 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 0304-3940 © 2010 Elsevier Ireland Ltd. Open access under CC BY license. doi:10.1016/j.neulet.2010.08.074 R.S. Swanwick et al. / Neuroscience Letters 486 (2010) 78–83 79 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 pro- teins 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
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