Limits...
Trafficking regulates the subcellular distribution of voltage-gated sodium channels in primary sensory neurons.

Bao L - Mol Pain (2015)

Bottom Line: Axonal transport and localization of Navs in afferent fibers involves the motor protein KIF5B and scaffold proteins, including contactin and PDZ domain containing 2.Localization of Nav1.6 to the nodes of Ranvier in myelinated fibers of primary sensory neurons requires node formation and the submembrane cytoskeletal protein complex.These findings inform our understanding of the molecular and cellular mechanisms underlying Nav trafficking in primary sensory neurons.

View Article: PubMed Central - PubMed

Affiliation: State Key Laboratory of Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 320 Yue Yang Road, Shanghai, 200031, China. baolan@sibcb.ac.cn.

ABSTRACT
Voltage-gated sodium channels (Navs) comprise at least nine pore-forming α subunits. Of these, Nav1.6, Nav1.7, Nav1.8 and Nav1.9 are the most frequently studied in primary sensory neurons located in the dorsal root ganglion and are mainly localized to the cytoplasm. A large pool of intracellular Navs raises the possibility that changes in Nav trafficking could alter channel function. The molecular mediators of Nav trafficking mainly consist of signals within the Navs themselves, interacting proteins and extracellular factors. The surface expression of Navs is achieved by escape from the endoplasmic reticulum and proteasome degradation, forward trafficking and plasma membrane anchoring, and it is also regulated by channel phosphorylation and ubiquitination in primary sensory neurons. Axonal transport and localization of Navs in afferent fibers involves the motor protein KIF5B and scaffold proteins, including contactin and PDZ domain containing 2. Localization of Nav1.6 to the nodes of Ranvier in myelinated fibers of primary sensory neurons requires node formation and the submembrane cytoskeletal protein complex. These findings inform our understanding of the molecular and cellular mechanisms underlying Nav trafficking in primary sensory neurons.

No MeSH data available.


Related in: MedlinePlus

Main steps that regulates the subcellular distribution of Navs in primary sensory neurons. The surface expression of Navs is achieved by escape from the endoplasmic reticulum and proteasome degradation, forward trafficking and plasma membrane anchoring in primary sensory neurons. Axonal transport and localization of Navs in afferent fibers involves motor proteins and scaffold proteins. Localization of Nav1.6 to the nodes of Ranvier in myelinated fibers of primary sensory neurons requires node formation and the submembrane cytoskeletal protein complex. The molecules listed are mostly positive regulators except NEDD4-2 that may impede forward trafficking of Nav1.7. However, the hypothesized roles of molecules with question mark during various steps of Nav trafficking in primary sensory neuron need to be proved
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

License 1 - License 2
getmorefigures.php?uid=PMC4590712&req=5

Fig2: Main steps that regulates the subcellular distribution of Navs in primary sensory neurons. The surface expression of Navs is achieved by escape from the endoplasmic reticulum and proteasome degradation, forward trafficking and plasma membrane anchoring in primary sensory neurons. Axonal transport and localization of Navs in afferent fibers involves motor proteins and scaffold proteins. Localization of Nav1.6 to the nodes of Ranvier in myelinated fibers of primary sensory neurons requires node formation and the submembrane cytoskeletal protein complex. The molecules listed are mostly positive regulators except NEDD4-2 that may impede forward trafficking of Nav1.7. However, the hypothesized roles of molecules with question mark during various steps of Nav trafficking in primary sensory neuron need to be proved

Mentions: High levels of Navs are not localized on the plasma membrane of primary sensory neuron [6–11, 20]. The trafficking of the channels could be impeded at various points along the secretory pathway, including in the ER, Golgi complex and vesicles (Fig. 2). Nav1.8 displays a reticulum-like distribution and colocalizes with calnexin, an ER marker, in transfected COS-7 cells [11]. Using CD8α and TFR1 as model molecules to screen potential ER-localization motifs and sequences, an RXR motif in the first intracellular loop of Nav1.8 and several transmembrane segments containing acidic amino acids were found to be responsible for its ER localization [11, 18]. The β3 subunit interacts with Nav1.8 and masks the RXR motif to promote surface expression of the channel [11]. Calnexin, an ER chaperone protein, interacts with the transmembrane segments containing the acidic amino acids and induces channel degradation through the proteasome pathway [18]. p11, annexin 2 light chain, binds to aa 74–103 in the N-terminus of Nav1.8 to promote translocation of the channel to the plasma membrane [8]. Specific knockout of p11 in nociceptive DRG neurons reduces the TTX-R sodium current density and causes a dramatic loss of membrane-associated Nav1.8 [21]. As p11 has been shown to mask an ER-localization signal in TASK-1 to promote the surface expression of that channel [22], the role of p11 in promoting Nav1.8 trafficking from the ER needs to be evaluated.Fig. 2


Trafficking regulates the subcellular distribution of voltage-gated sodium channels in primary sensory neurons.

Bao L - Mol Pain (2015)

Main steps that regulates the subcellular distribution of Navs in primary sensory neurons. The surface expression of Navs is achieved by escape from the endoplasmic reticulum and proteasome degradation, forward trafficking and plasma membrane anchoring in primary sensory neurons. Axonal transport and localization of Navs in afferent fibers involves motor proteins and scaffold proteins. Localization of Nav1.6 to the nodes of Ranvier in myelinated fibers of primary sensory neurons requires node formation and the submembrane cytoskeletal protein complex. The molecules listed are mostly positive regulators except NEDD4-2 that may impede forward trafficking of Nav1.7. However, the hypothesized roles of molecules with question mark during various steps of Nav trafficking in primary sensory neuron need to be proved
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4590712&req=5

Fig2: Main steps that regulates the subcellular distribution of Navs in primary sensory neurons. The surface expression of Navs is achieved by escape from the endoplasmic reticulum and proteasome degradation, forward trafficking and plasma membrane anchoring in primary sensory neurons. Axonal transport and localization of Navs in afferent fibers involves motor proteins and scaffold proteins. Localization of Nav1.6 to the nodes of Ranvier in myelinated fibers of primary sensory neurons requires node formation and the submembrane cytoskeletal protein complex. The molecules listed are mostly positive regulators except NEDD4-2 that may impede forward trafficking of Nav1.7. However, the hypothesized roles of molecules with question mark during various steps of Nav trafficking in primary sensory neuron need to be proved
Mentions: High levels of Navs are not localized on the plasma membrane of primary sensory neuron [6–11, 20]. The trafficking of the channels could be impeded at various points along the secretory pathway, including in the ER, Golgi complex and vesicles (Fig. 2). Nav1.8 displays a reticulum-like distribution and colocalizes with calnexin, an ER marker, in transfected COS-7 cells [11]. Using CD8α and TFR1 as model molecules to screen potential ER-localization motifs and sequences, an RXR motif in the first intracellular loop of Nav1.8 and several transmembrane segments containing acidic amino acids were found to be responsible for its ER localization [11, 18]. The β3 subunit interacts with Nav1.8 and masks the RXR motif to promote surface expression of the channel [11]. Calnexin, an ER chaperone protein, interacts with the transmembrane segments containing the acidic amino acids and induces channel degradation through the proteasome pathway [18]. p11, annexin 2 light chain, binds to aa 74–103 in the N-terminus of Nav1.8 to promote translocation of the channel to the plasma membrane [8]. Specific knockout of p11 in nociceptive DRG neurons reduces the TTX-R sodium current density and causes a dramatic loss of membrane-associated Nav1.8 [21]. As p11 has been shown to mask an ER-localization signal in TASK-1 to promote the surface expression of that channel [22], the role of p11 in promoting Nav1.8 trafficking from the ER needs to be evaluated.Fig. 2

Bottom Line: Axonal transport and localization of Navs in afferent fibers involves the motor protein KIF5B and scaffold proteins, including contactin and PDZ domain containing 2.Localization of Nav1.6 to the nodes of Ranvier in myelinated fibers of primary sensory neurons requires node formation and the submembrane cytoskeletal protein complex.These findings inform our understanding of the molecular and cellular mechanisms underlying Nav trafficking in primary sensory neurons.

View Article: PubMed Central - PubMed

Affiliation: State Key Laboratory of Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 320 Yue Yang Road, Shanghai, 200031, China. baolan@sibcb.ac.cn.

ABSTRACT
Voltage-gated sodium channels (Navs) comprise at least nine pore-forming α subunits. Of these, Nav1.6, Nav1.7, Nav1.8 and Nav1.9 are the most frequently studied in primary sensory neurons located in the dorsal root ganglion and are mainly localized to the cytoplasm. A large pool of intracellular Navs raises the possibility that changes in Nav trafficking could alter channel function. The molecular mediators of Nav trafficking mainly consist of signals within the Navs themselves, interacting proteins and extracellular factors. The surface expression of Navs is achieved by escape from the endoplasmic reticulum and proteasome degradation, forward trafficking and plasma membrane anchoring, and it is also regulated by channel phosphorylation and ubiquitination in primary sensory neurons. Axonal transport and localization of Navs in afferent fibers involves the motor protein KIF5B and scaffold proteins, including contactin and PDZ domain containing 2. Localization of Nav1.6 to the nodes of Ranvier in myelinated fibers of primary sensory neurons requires node formation and the submembrane cytoskeletal protein complex. These findings inform our understanding of the molecular and cellular mechanisms underlying Nav trafficking in primary sensory neurons.

No MeSH data available.


Related in: MedlinePlus