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Juxtaparanodal clustering of Shaker-like K+ channels in myelinated axons depends on Caspr2 and TAG-1.

Poliak S, Salomon D, Elhanany H, Sabanay H, Kiernan B, Pevny L, Stewart CL, Xu X, Chiu SY, Shrager P, Furley AJ, Peles E - J. Cell Biol. (2003)

Bottom Line: In myelinated axons, K+ channels are concealed under the myelin sheath in the juxtaparanodal region, where they are associated with Caspr2, a member of the neurexin superfamily.Deletion of Caspr2 in mice by gene targeting revealed that it is required to maintain K+ channels at this location.These results demonstrate that Caspr2 and TAG-1 form a scaffold that is necessary to maintain K+ channels at the juxtaparanodal region, suggesting that axon-glia interactions mediated by these proteins allow myelinating glial cells to organize ion channels in the underlying axonal membrane.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular Cell Biology, The Weizmann Institute of Science, Rehovot 76100, Israel.

ABSTRACT
In myelinated axons, K+ channels are concealed under the myelin sheath in the juxtaparanodal region, where they are associated with Caspr2, a member of the neurexin superfamily. Deletion of Caspr2 in mice by gene targeting revealed that it is required to maintain K+ channels at this location. Furthermore, we show that the localization of Caspr2 and clustering of K+ channels at the juxtaparanodal region depends on the presence of TAG-1, an immunoglobulin-like cell adhesion molecule that binds Caspr2. These results demonstrate that Caspr2 and TAG-1 form a scaffold that is necessary to maintain K+ channels at the juxtaparanodal region, suggesting that axon-glia interactions mediated by these proteins allow myelinating glial cells to organize ion channels in the underlying axonal membrane.

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Schematic model describing molecular interactions at the juxtaparanodal region of myelinated axons. A cis complex of Caspr2 and TAG-1 is present at the axolemma. Homophilic interactions mediate the binding of this complex to glial TAG-1 present on the adaxonal membrane. The association of Caspr2 and K+ channels involves the PDZ-binding sequence of both proteins, and is likely mediated by yet unidentified PDZ domain–containing protein/s. The juxtaparanodes contain PSD-95, which binds K+ channels, but not Caspr2. The cytoplasmic region of Caspr2 also binds to protein 4.1B present at this site, which may connect the whole complex to the axonal cytoskeleton. PDZ, PSD-95/discs large/zona occludens 1; GUK, guanylate kinase; SH3, Src homology 3; MBD, membrane-binding domain.
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fig9: Schematic model describing molecular interactions at the juxtaparanodal region of myelinated axons. A cis complex of Caspr2 and TAG-1 is present at the axolemma. Homophilic interactions mediate the binding of this complex to glial TAG-1 present on the adaxonal membrane. The association of Caspr2 and K+ channels involves the PDZ-binding sequence of both proteins, and is likely mediated by yet unidentified PDZ domain–containing protein/s. The juxtaparanodes contain PSD-95, which binds K+ channels, but not Caspr2. The cytoplasmic region of Caspr2 also binds to protein 4.1B present at this site, which may connect the whole complex to the axonal cytoskeleton. PDZ, PSD-95/discs large/zona occludens 1; GUK, guanylate kinase; SH3, Src homology 3; MBD, membrane-binding domain.

Mentions: The localization of Caspr2 at the juxtaparanodes and the clustering of K+ channels depend on the presence of TAG-1, a GPI-anchored cell adhesion molecule from the immunoglobulin superfamily (Furley et al., 1990). We demonstrated that Caspr2 directly associates with TAG-1 in rat brain and that the localization of both proteins at the juxtaparanodes is interdependent, suggesting that the proteins form a scaffold that is essential for the clustering of K+ channels at this site. In agreement, we found that both Caspr2 and TAG-1 antibodies coimmunoprecipitate Kv1.2 from rat brain. It was previously reported that TAG-1 is expressed by myelinating Schwann cells and oligodendrocytes and is localized at the juxtaparanodes in myelinated nerves (Traka et al., 2002). However, the precise location of this adhesion molecule at the juxtaparanodal region is still unknown. In particular, it is not clear whether it is found only on the glial membrane, the axolemma, or both. Using a tau-lacZ marker under the control of TAG-1 promoter, we show that in the PNS it is expressed by DRG neurons and their processes, as well as by myelinating Schwann cells. Similarly, in the adult rat spinal cord, TAG-1 was found in motor neurons, as well as in oligodendrocytes (Traka et al., 2002). These results indicate that TAG-1 is expressed by both myelinating glia and the neurons they ensheath. TAG-1 and Caspr2 were associated in transfected cells and a soluble TAG-1–Fc bound to cells expressing TAG-1 or Caspr2/TAG-1, but not to Caspr2 alone, indicating that these molecules are able to form a cis (but not a trans) complex. Thus, our results suggest that these molecules most likely generate a complex consisting of a glial TAG-1 molecule and an axonal Caspr2/TAG-1 heterodimer through homophilic binding of TAG-1 (Fig. 9).


Juxtaparanodal clustering of Shaker-like K+ channels in myelinated axons depends on Caspr2 and TAG-1.

Poliak S, Salomon D, Elhanany H, Sabanay H, Kiernan B, Pevny L, Stewart CL, Xu X, Chiu SY, Shrager P, Furley AJ, Peles E - J. Cell Biol. (2003)

Schematic model describing molecular interactions at the juxtaparanodal region of myelinated axons. A cis complex of Caspr2 and TAG-1 is present at the axolemma. Homophilic interactions mediate the binding of this complex to glial TAG-1 present on the adaxonal membrane. The association of Caspr2 and K+ channels involves the PDZ-binding sequence of both proteins, and is likely mediated by yet unidentified PDZ domain–containing protein/s. The juxtaparanodes contain PSD-95, which binds K+ channels, but not Caspr2. The cytoplasmic region of Caspr2 also binds to protein 4.1B present at this site, which may connect the whole complex to the axonal cytoskeleton. PDZ, PSD-95/discs large/zona occludens 1; GUK, guanylate kinase; SH3, Src homology 3; MBD, membrane-binding domain.
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Related In: Results  -  Collection

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fig9: Schematic model describing molecular interactions at the juxtaparanodal region of myelinated axons. A cis complex of Caspr2 and TAG-1 is present at the axolemma. Homophilic interactions mediate the binding of this complex to glial TAG-1 present on the adaxonal membrane. The association of Caspr2 and K+ channels involves the PDZ-binding sequence of both proteins, and is likely mediated by yet unidentified PDZ domain–containing protein/s. The juxtaparanodes contain PSD-95, which binds K+ channels, but not Caspr2. The cytoplasmic region of Caspr2 also binds to protein 4.1B present at this site, which may connect the whole complex to the axonal cytoskeleton. PDZ, PSD-95/discs large/zona occludens 1; GUK, guanylate kinase; SH3, Src homology 3; MBD, membrane-binding domain.
Mentions: The localization of Caspr2 at the juxtaparanodes and the clustering of K+ channels depend on the presence of TAG-1, a GPI-anchored cell adhesion molecule from the immunoglobulin superfamily (Furley et al., 1990). We demonstrated that Caspr2 directly associates with TAG-1 in rat brain and that the localization of both proteins at the juxtaparanodes is interdependent, suggesting that the proteins form a scaffold that is essential for the clustering of K+ channels at this site. In agreement, we found that both Caspr2 and TAG-1 antibodies coimmunoprecipitate Kv1.2 from rat brain. It was previously reported that TAG-1 is expressed by myelinating Schwann cells and oligodendrocytes and is localized at the juxtaparanodes in myelinated nerves (Traka et al., 2002). However, the precise location of this adhesion molecule at the juxtaparanodal region is still unknown. In particular, it is not clear whether it is found only on the glial membrane, the axolemma, or both. Using a tau-lacZ marker under the control of TAG-1 promoter, we show that in the PNS it is expressed by DRG neurons and their processes, as well as by myelinating Schwann cells. Similarly, in the adult rat spinal cord, TAG-1 was found in motor neurons, as well as in oligodendrocytes (Traka et al., 2002). These results indicate that TAG-1 is expressed by both myelinating glia and the neurons they ensheath. TAG-1 and Caspr2 were associated in transfected cells and a soluble TAG-1–Fc bound to cells expressing TAG-1 or Caspr2/TAG-1, but not to Caspr2 alone, indicating that these molecules are able to form a cis (but not a trans) complex. Thus, our results suggest that these molecules most likely generate a complex consisting of a glial TAG-1 molecule and an axonal Caspr2/TAG-1 heterodimer through homophilic binding of TAG-1 (Fig. 9).

Bottom Line: In myelinated axons, K+ channels are concealed under the myelin sheath in the juxtaparanodal region, where they are associated with Caspr2, a member of the neurexin superfamily.Deletion of Caspr2 in mice by gene targeting revealed that it is required to maintain K+ channels at this location.These results demonstrate that Caspr2 and TAG-1 form a scaffold that is necessary to maintain K+ channels at the juxtaparanodal region, suggesting that axon-glia interactions mediated by these proteins allow myelinating glial cells to organize ion channels in the underlying axonal membrane.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular Cell Biology, The Weizmann Institute of Science, Rehovot 76100, Israel.

ABSTRACT
In myelinated axons, K+ channels are concealed under the myelin sheath in the juxtaparanodal region, where they are associated with Caspr2, a member of the neurexin superfamily. Deletion of Caspr2 in mice by gene targeting revealed that it is required to maintain K+ channels at this location. Furthermore, we show that the localization of Caspr2 and clustering of K+ channels at the juxtaparanodal region depends on the presence of TAG-1, an immunoglobulin-like cell adhesion molecule that binds Caspr2. These results demonstrate that Caspr2 and TAG-1 form a scaffold that is necessary to maintain K+ channels at the juxtaparanodal region, suggesting that axon-glia interactions mediated by these proteins allow myelinating glial cells to organize ion channels in the underlying axonal membrane.

Show MeSH
Related in: MedlinePlus