Determinants of voltage-gated sodium channel clustering in neurons

Leterrier, Christophe; Brachet, Anna; Vacher, Hélène

doi:10.1016/j.semcdb.2010.09.014

Cited by 35 publications

(37 citation statements)

References 84 publications

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“…Numerous studies suggest that these three mechanisms are alternative or complementary to induce nodal assembly (8,9). Direct axoglial contacts established at the paranodal junctions have been suggested to induce nodal protein clustering through restriction of their diffusion (12,13).…”

Section: Discussion Prenodal Clustering Occurs On Gabaergic Interneurmentioning

confidence: 99%

Acceleration of conduction velocity linked to clustering of nodal components precedes myelination

Freeman

Desmazières

Simonnet

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

128

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High-density accumulation of voltage-gated sodium (Na v ) channels at nodes of Ranvier ensures rapid saltatory conduction along myelinated axons. To gain insight into mechanisms of node assembly in the CNS, we focused on early steps of nodal protein clustering. We show in hippocampal cultures that prenodes (i.e., clusters of Na v channels colocalizing with the scaffold protein ankyrinG and nodal cell adhesion molecules) are detected before myelin deposition along axons. These clusters can be induced on purified neurons by addition of oligodendroglial-secreted factor(s), whereas ankyrinG silencing prevents their formation. The Na v isoforms Na v 1.1, Na v 1.2, and Na v 1.6 are detected at prenodes, with Na v 1.6 progressively replacing Na v 1.2 over time in hippocampal neurons cultured with oligodendrocytes and astrocytes. However, the oligodendrocyte-secreted factor(s) can induce the clustering of Na v 1.1 and Na v 1.2 but not of Na v 1.6 on purified neurons. We observed that prenodes are restricted to GABAergic neurons, whereas clustering of nodal proteins only occurs concomitantly with myelin ensheathment on pyramidal neurons, implying separate mechanisms of assembly among different neuronal subpopulations. To address the functional significance of these early clusters, we used single-axon electrophysiological recordings in vitro and showed that prenode formation is sufficient to accelerate the speed of axonal conduction before myelination. Finally, we provide evidence that prenodal clusters are also detected in vivo before myelination, further strengthening their physiological relevance.oltage-gated sodium (Na v ) channels are highly enriched at the axon initial segment (AIS) and the node of Ranvier, allowing generation and rapid propagation of action potentials by saltatory conduction in myelinated fibers. These axonal domains also contain cell adhesion molecules [e.g., neurofascin 186 (Nfasc186)] and the scaffolding proteins ankyrinG (AnkG) and βIV spectrin, which provide a potential link with the actin cytoskeleton (1). Flanking the nodes are the paranodes, where axoglial junctions between paranodal myelin loops and the axon are formed through interactions between axonal contactinassociated protein (Caspr)/contactin and glial Nfasc155 (2, 3). Although the mechanisms of nodal assembly are best characterized in the peripheral nervous system (4-9), less is known about the cellular and molecular mechanisms underlying node assembly in the CNS. ECM proteins, adhesion molecules, such as Nfasc186, and also, axoglial paranodal junctions have been shown to trigger CNS nodal clustering, although their respective roles remain uncertain (10-19). Moreover, axonal clustering of Na v channels before myelin deposition and oligodendroglial contact has been shown to occur in retinal ganglion cell (RGC) cultures, where these clusters were induced by oligodendroglial-secreted factor(s) (20, 21).Here, we have investigated the cellular and molecular mechanisms underlying nodal protein assembly in hippocampal neuron cultures. We ...

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Section: Discussion Prenodal Clustering Occurs On Gabaergic Interneurmentioning

confidence: 99%

Acceleration of conduction velocity linked to clustering of nodal components precedes myelination

Freeman

Desmazières

Simonnet

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

128

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“…The mechanisms for the targeting of AIS proteins are the subject of an ongoing debate. On the one hand, a ''diffusion trapping'' model has been proposed in which Nav and KCNQ2/3 channels are transported to the plasma membrane and diffuse to the AIS where they are immobilized by ankG (Leterrier et al, 2011a;Xu and Cooper, 2015). On the other hand, a ''direct insertion'' model was put forward in which Nav channels are directly targeted to the AIS where they are immediately immobilized (Barry et al, 2014;Akin et al, 2015).…”

Section: Discussionmentioning

confidence: 99%

Ankyrin G membrane partners drive the establishment and maintenance of the axon initial segment

Leterrier

Clerc

Rueda-Boroni

et al. 2016

Preprint

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The axon initial segment (AIS) is a highly specialized neuronal compartment that plays a key role in neuronal development and excitability. It concentrates multiple membrane proteins such as ion channels and cell adhesion molecules (CAMs) that are recruited to the AIS by the scaffold protein ankyrin G (ankG). The crucial function of ankG in the anchoring of AIS membrane components is well established, but a reciprocal role of membrane partners in ankG targeting and stabilization remained elusive. In rat cultured hippocampal neurons and cortical organotypic slices, we found that shRNA-mediated knockdown of ankG membrane partners (voltage-gated sodium channels (Nav) or neurofascin-186) led to a decrease of ankG concentration and perturbed the AIS formation and maintenance. These effects were rescued by expressing a recombinant AIS-targeted Nav or by a minimal construct containing the ankyrin-binding domain of Nav1.2 and a membrane anchor (mABD). Moreover, overexpressing mABD in mature neurons led to ankG mislocalization. Altogether, these results demonstrate that a tight and precocious association of ankG with its membrane partners is a key step for the establishment and maintenance of the AIS.

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“…There remains some controversy, however, as to what extent the density of functional Na + channels is greater in the AIS than in the soma [10,[49][50][51][52] . Within the AIS and in the nodes, these channels are anchored to AnkG by the binding motif in the II/III loop of the α subunit [53] . In other areas of the cell, the Na v channels are prone to elimination by endocytosis [54] .…”

Section: Na + Channelsmentioning

confidence: 99%

Functional implications of axon initial segment cytoskeletal disruption in stroke

Stoler

Fleidervish

2015

Acta Pharmacol Sin

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Axon initial segment (AIS) is the proximal part of the axon, which is not covered with a myelin sheath and possesses a distinctive, specialized assembly of voltage-gated ion channels and associated proteins. AIS plays critical roles in synaptic integration and action potential generation in central neurons. Recent evidence shows that stroke causes rapid, irreversible calpain-mediated proteolysis of the AIS cytoskeleton of neurons surrounding the ischemic necrotic core. A better understanding of the molecular mechanisms underlying this "non-lethal" neuronal damage might provide new therapeutic strategies for improving stroke outcome. Here, we present a brief overview of the structure and function of the AIS. We then discuss possible mechanisms underlying stroke-induced AIS damage, including the roles of calpains and possible sources of Ca 2+ ions, which are necessary for the activation of calpains. Finally, we discuss the potential functional implications of the loss of the AIS cytoskeleton and ion channel clusters for neuronal excitability.

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Determinants of voltage-gated sodium channel clustering in neurons

Cited by 35 publications

References 84 publications

Acceleration of conduction velocity linked to clustering of nodal components precedes myelination

Acceleration of conduction velocity linked to clustering of nodal components precedes myelination

Ankyrin G membrane partners drive the establishment and maintenance of the axon initial segment

Functional implications of axon initial segment cytoskeletal disruption in stroke

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