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Molecular organization of the AIS and peripheral node of Ranvier. (A) Organization of cell adhesion molecules and ion channels at the AIS. AnkyrinG and ßIVspectrin assemble as a submembrane scaffold that plays a critical role in the recruitment of the voltage-gated Nav1.6 and Kv7.2/7.3 channels at the AIS, together with the cell adhesion molecules Neurofascin186 (NF186) and NrCAM. The Kv1.1/1.2 complex is enriched at the AIS exhibiting a distal distribution and is associated with PSD93. Caspr2 and contactin2 are also enriched at the AIS. ADAM22 is required for the recruitment of LGI1, but is dispensable for the concentration of Kv1 at the AIS. (B) Distinct complexes of cell adhesion molecules and channels are segregated at the different domains of myelinated axons, the node of Ranvier, paranode, juxtaparanode, and internode as shown here for the PNS. At the nodal gap, the voltage-gated Nav1.6 and Kv7.2/7.3 channels are recruited via their ankyrinG-binding sites together with Neurofascin186 and NrCAM. Neurofascin186 is clustered at the node first through its interaction with gliomedin and NrCAM on Schwann cell microvilli. The two-pore-domain K + channels TREK1/TRAAK are new players at the node. The voltage-gated Kv1.1/1.2 channels are localized at the juxtaparanodes associated in complex with cell adhesion molecules. The cis complex of Caspr2 and Contactin2 interacts in trans with Contactin2 on the myelin. ADAM22, ADAM23, and LGI4 have been also localized at the juxtaparanodes. The submembrane cytoskeleton of the juxtaparanodes includes 4.1B, αII/ßII spectrin, PSD93, and PSD95. At the internode, the axonal cell adhesion molecules Necl1 and Necl2 interact with 4.1B and serve as partners for glial Necl4.
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The precise axonal distribution of specific potassium channels is known to secure the shape and frequency of action potentials in myelinated fibers. The low-threshold voltage-gated Kv1 channels located at the axon initial segment have a significant influence on spike initiation and waveform. Their role remains partially understood at the juxtaparan...
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Context 1
... mechanisms that control the precise axonal distribution of ion channels have been the subject of intense investigations (Figure 2A). A common ankyrinG-based mechanism retains the Nav1 and Kv7 channels at the nodes of Ranvier and AIS. ...
Context 2
... juxtaparanodes are membrane axonal domains that are enriched in Kv1.1/Kv1.2 channels located under the compact myelin at the borders of the paranodes ( Figure 2B). In contrast with the paranodes that show a very characteristic ultrastructural feature with intermembrane transverse bands forming the septate-like junctions between the axolemma and terminal myelin loops, the juxtaparanodes do not display any noticeable junctional specialization. ...
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... the role of axo-glial interactions, the cortical cytoskeleton plays an important role in the segregation of membrane proteins at the different subdomains of the node of Ranvier ( Figure 2B). Band 4.1B belongs to a family of proteins that anchor membrane receptors to the cortical actin/spectrin cytoskeleton. ...
Citations
... encoded by KCNA2) belongs to the Kv1 family, which has eight members (Kv1. [1][2][3][4][5][6][7][8]. Kv1.2 channel is composed of four alpha-subunits with six transmembrane domains (S1-S6), in which S4 is the voltage sensor, and S5 and S6 constitute the pore region [1]. ...
... Döring JH et al. summarized KCNA2 phenotypes and genotypes from all published cases with epilepsy [7]. Pinatel D et al. reviewed and discussed the assembly and function of the juxtaparanodal (JXP) Kv1 complex in health, de-myelinating neuropathy, and autoimmune diseases [8]. Catacuzzeno L et al. reviewed the structure of the Kv channel emphasizing the role of Kv1.2/2.1 chimera channel [2]. ...
... The JXP are membrane bound axonal domains that contain Kv1.1/Kv1.2 channels situated under the myelin at the paranodes borders [8]. In the CNS, Kv1.2 channels are mainly expressed in the pons, medulla, cerebellum, hippocampus [9], thalamus, cerebral cortex, and spinal cord [10,11]. ...
Potassium voltage-gated channel subfamily a member 2 (Kv1.2, encoded by KCNA2) is highly expressed in the central and peripheral nervous systems. Based on the patch clamp studies, gain-of function (GOF), loss-of-function (LOF), and a mixed type (GOF/LOF) variants can cause different conditions/disorders. KCNA2-related neurological diseases include epilepsy, intellectual disability (ID), attention deficit/hyperactive disorder (ADHD), autism spectrum disorder (ASD), pain as well as autoimmune and movement disorders. Currently, the molecular mechanisms for the reported variants in causing diverse disorders are unknown. Consequently, this review brings up to date the related information regarding the structure and function of Kv1.2 channel, expression patterns, neuronal localizations, and tetramerization as well as important cell and animal models. In addition, it provides updates on human genetic variants, genotype–phenotype correlations especially highlighting the deep insight into clinical prognosis of KCNA2-related developmental and epileptic encephalopathy, mechanisms, and the potential treatment targets for all KCNA2-related neurological disorders.
... These channels are then rapidly inactivated allowing potassium channels to repolarize the axon. Different voltage-gated K + channels (KV3 and Kv7 channels) as well as mechano-and thermo-sensitive K + channels, two-poredomain potassium K2P channels, actively drive repolarization (or falling phase) at the nodes [28][29][30], wherein Kv1 channels located in the juxtaparanode contribute to the refractory period enabling high frequency firing [31,32]. Directly underneath the sheath, OL expression of inwardly rectifying K + channels (Kir channels) allows K + buffering which probably help establish axolemma resting potential and excitability, especially in white matter tracts where astrocytes have limited access to axons [33]. ...
In vertebrates, oligodendrocytes (OLs) are glial cells of the central nervous system (CNS) responsible for the formation of the myelin sheath that surrounds the axons of neurons. The myelin sheath plays a crucial role in the transmission of neuronal information by promoting the rapid saltatory conduction of action potentials and providing neurons with structural and metabolic support. Saltatory conduction, first described in the peripheral nervous system (PNS), is now generally recognized as a universal evolutionary innovation to respond quickly to the environment: myelin helps us think and act fast. However, the function of myelin in the CNS, particularly in the brain, is not necessarily to act quickly, but rather to act correctly. In this respect, myelin should primarily play a role in synchronizing the different neuronal networks, a synchrony that occurs in the form of oscillations (or rhythms) relevant for specific information processing. Interestingly, myelin has been directly involved in different types of cognitive processes relying on brain oscillations, and myelin plasticity is currently considered to be part of the fundamental mechanisms for memory formation and maintenance. However, despite ample evidence showing the involvement of myelin in cognition and neurodevelopmental disorders characterized by cognitive impairments, the link between myelin, brain oscillations, cognition and disease is not yet fully understood. In this review, we aim to highlight what is known and what remains to be explored to understand the role of myelin in high order brain processes.
... transmission and limit abnormal axonal firing [12][13][14] , with these controls being compromised by pharmacological inhibition or by loss-offunction mutations 10 . ...
There are currently no drugs known to rescue the function of Kv1.1 voltage-gated potassium channels carrying loss-of-function sequence variants underlying the inherited movement disorder, Episodic Ataxia 1 (EA1). The Kwakwaka’wakw First Nations of the Pacific Northwest Coast used Fucus gardneri (bladderwrack kelp), Physocarpus capitatus (Pacific ninebark) and Urtica dioica (common nettle) to treat locomotor ataxia. Here, we show that extracts of these plants enhance wild-type Kv1.1 current, especially at subthreshold potentials. Screening of their constituents revealed that gallic acid and tannic acid similarly augment wild-type Kv1.1 current, with submicromolar potency. Crucially, the extracts and their constituents also enhance activity of Kv1.1 channels containing EA1-linked sequence variants. Molecular dynamics simulations reveal that gallic acid augments Kv1.1 activity via a small-molecule binding site in the extracellular S1-S2 linker. Thus, traditional Native American ataxia treatments utilize a molecular mechanistic foundation that can inform small-molecule approaches to therapeutically correcting EA1 and potentially other Kv1.1-linked channelopathies.
... Kv1 channels are mainly expressed in axons. In myelinated axons, they accumulate at the JXP into multi-protein complexes that consist of, in addition to their β-subunits, the cell adhesion molecules Contactin-associated protein2 (CASPR2), Contactin2 (CNTN-2, also called TAG-1), ADAM22 (A Disintegrin And Metalloproteinase22), the membraneassociated guanylate kinases (MAGUKs) PSD93 (DLG2) and PSD95 (DLG4) and the adaptor protein 4.1B (Pinatel and Faivre-Sarrailh, 2020). TAG-1 is present in both the glial inner myelin membrane (adaxonal) and axonal membrane where it interacts with axonal CASPR2, forming a link between the myelin and axonal membranes (Traka et al., 2003;. ...
... A large body of work on NOR formation, and JXP/Kv1 formation over the last two decades has led to a model in which CASPR2/TAG-1 interactions and linkage to the underlying cytoskeleton through CASPR2 cytoplasmic domain interactions with 4.1B was responsible for the accumulation and maintenance of the Kv1 channels at the JXP (Poliak et al., 2001;Traka et al., 2003;Horresh et al., 2010;Ogawa et al., 2008;Pinatel et al., 2017;Pinatel and Faivre-Sarrailh, 2020;Poliak and Peles, 2003). Later studies (see also Fig. 6) that demonstrated that a large proportion of developing myelinated axons in Caspr2 −/− animals do have detectable levels of Kv1 channels in their nascent juxtaparanodes, required modification of this model to one involving alternative mechanisms for clustering Kv1 channels (Ogawa et al., 2010;Saifetiarova et al., 2017). ...
Along myelinated axons, Shaker-type potassium channels (Kv1) accumulate at high density in the juxtaparanodal region, directly adjacent to the paranodal axon–glia junctions that flank the nodes of Ranvier. However, the mechanisms that control the clustering of Kv1 channels, as well as their function at this site, are still poorly understood. Here we demonstrate that axonal ADAM23 is essential for both the accumulation and stability of juxtaparanodal Kv1 complexes. The function of ADAM23 is critically dependent on its interaction with its extracellular ligands LGI2 and LGI3. Furthermore, we demonstrate that juxtaparanodal Kv1 complexes affect the refractory period, thus enabling high-frequency burst firing of action potentials. Our findings not only reveal a previously unknown molecular pathway that regulates Kv1 channel clustering, but they also demonstrate that the juxtaparanodal Kv1 channels that are concealed below the myelin sheath, play a significant role in modifying axonal physiology.
... In addition to the direct targeting of K V 1 channel activity to modulate pain, the involvement of shaker-related channels can also be modulated. Alterations in adhesion protein CASPR2, which anchors K V 1.1, K V 1.2 and K V 1.6 subunits at juxta-paranodes of primary sensory axons, can regulate the function of K V 1 channels in myelinated axons 88 . Induction of pain-related hypersensitivity in mice without neural injury by human CASPR2 auto-antibodies 89 suggests that generic targeting of this regulatory mechanism might be relevant to pain therapy. ...
With sweeping advances in precision delivery systems and manipulation of the genomes and transcriptomes of various cell types, medical biotechnology offers unprecedented selectivity for and control of a wide variety of biological processes, forging new opportunities for therapeutic interventions. This perspective summarizes state-of-the-art gene therapies enabled by recent innovations, with an emphasis on the expanding universe of molecular targets that govern the activity and function of primary sensory neurons and which might be exploited to effectively treat chronic pain. Sections
... The core of this structure is ankyrin G (ANK3), a member of the family of proteins that mediate the attachment of membrane proteins to the cytoskeleton, concentrating specifically at the AIS and nodes of Ranvier [15][16][17]. Other ankyrins, G and R, are found in the Ranvier junction, while B is localized mainly in the internode region of the axon [16,17]. ...
... The core of this structure is ankyrin G (ANK3), a member of the family of proteins that mediate the attachment of membrane proteins to the cytoskeleton, concentrating specifically at the AIS and nodes of Ranvier [15][16][17]. Other ankyrins, G and R, are found in the Ranvier junction, while B is localized mainly in the internode region of the axon [16,17]. Due to its modular structure, ankyrin G organizes the AIS scaffold [18]. ...
... The JXP is adjacent to the PNJ, and its organization depends upon the barrier formed by the PNJ on the one side and the unique JXP membrane complex and its linkage to the cytoskeleton on the other ( Figure 4) [16,31]. ...
The diagnosis of chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is based on a combination of clinical, electrodiagnostic and laboratory features. The different entities of the disease include chronic immune sensory polyradiculopathy (CISP) and autoimmune nodopathies. It is debatable whether CIDP occurring in the course of other conditions, i.e., monoclonal IgG or IgA gammopathy, should be treated as a separate disease entity from idiopathic CIDP. This study aims to evaluate the molecular differences of the nodes of Ranvier and the initial axon segment (AIS) and juxtaparanode region (JXP) as the potential cause of phenotypic variation of CIDP while also seeking new pathomechanisms since JXP is sequestered behind the paranode and autoantibodies may not access the site easily. The authors initially present the structure of the different parts of the neuron and its functional significance, then discuss the problem of whether damage to the juxtaparanodal region, Schwann cells and axons could cause CIDP or if these damages should be separated as separate disease entities. In particular, AIS’s importance for modulating neural excitability and carrying out transport along the axon is highlighted. The disclosure of specific pathomechanisms, including novel target antigens, in the heterogeneous CIDP syndrome is important for diagnosing and treating these patients.
... Motor neurons have heterogeneous axon initial segments (AISs), which underlie different spiking properties. Duflocq et al. identified a hemi-node-type organization in all α-motor neurons, with a contact-related protein (Caspr)+ paranode and a Caspr2+ and Kv1+ paranode compartment, identified as para-AIS and juxtapara (JXP)-AIS, adjacent to the AIS where the myelin sheath begins, which might limit some AIS plasticity [64]. Protein 4.1B plays a key role in ensuring the proper molecular compartmentalization of this hemi-node-type region [64,80,81]. ...
... Duflocq et al. identified a hemi-node-type organization in all α-motor neurons, with a contact-related protein (Caspr)+ paranode and a Caspr2+ and Kv1+ paranode compartment, identified as para-AIS and juxtapara (JXP)-AIS, adjacent to the AIS where the myelin sheath begins, which might limit some AIS plasticity [64]. Protein 4.1B plays a key role in ensuring the proper molecular compartmentalization of this hemi-node-type region [64,80,81]. ...
Chronic inflammatory demyelinating polyneuropathy (CIDP) is the most common form of autoimmune polyneuropathy. It is a chronic disease and may be monophasic, progressive or recurrent with exacerbations and incomplete remissions, causing accumulating disability. In recent years, there has been rapid progress in understanding the background of CIDP, which allowed us to distinguish specific phenotypes of this disease. This in turn allowed us to better understand the mechanism of response or non-response to various forms of therapy. On the basis of a review of the relevant literature, the authors present the current state of knowledge concerning the pathophysiology of the different clinical phenotypes of CIDP as well as ongoing research in this field, with reference to key points of immune-mediated processes involved in the background of CIDP.
... Anchoring of the myelin paranodal loops by adhesion molecules and their associated cytoskeletal linker proteins in both the glial and axonal membranes at the paranode segregate and condense the ion channels (Pinatel & Faivre-Sarrailh, 2021;Rasband & Peles, 2021). Of note to our review, disruption to the expression of the paranodal axo-glial membrane protein complex composed of glial Neurofascin 155 (NF155), axonal contactin-associated protein (Caspr) and Contactin markedly alters the normal conformation of the NoR (Bhat et al., 2001;Boyle et al., 2001;Pillai et al., 2009). ...
Gangliosides are a family of sialic acid containing glycosphingolipids highly enriched in plasma membranes of the vertebrate nervous system. They are functionally diverse in modulating nervous system integrity, notably at the node of Ranvier, and also act as receptors for many ligands including toxins and autoantibodies. They are synthesised in a stepwise manner by groups of glycosyl- and sialyltransferases in a developmentally and tissue regulated manner. In this review, we summarise and discuss data derived from transgenic mice with different transferase deficiencies that have been used to determine the role of glycolipids in the organisation of the node of Ranvier. Understanding their role at this specialised functional site is crucial to determining differential pathophysiology following directed genetic or autoimmune injury to peripheral nerve nodal or paranodal domains, and revealing the downstream consequences of axo-glial disruption.
... Juxtaparanodes are axonal domains adjacent to paranodes wrapped with compact myelin sheaths. These regions retain high densities of Kv channels from the Shaker family Kv1.1 and Kv1.2 (Pinatel and Faivre-Sarrailh, 2021). During development, Kv1.1 and Kv1.2 are transiently expressed both in the nodal gap and in paranodes where they most likely prevent aberrant excitation before assembly of paranodal junctions (Vabnick et al., 1999). ...
... Because residual Kv1 expression has been reported upon Caspr2 or Contactin-2 knock-out, other mechanisms may segregate Kv1 at juxtaparanodes. They may be mediated by additional proteins that are also enriched in these regions: ADAM22, a transmembrane receptor known to interact with Kv1 channels and the MAGuK scaffolding guanylate kinases PSD-93 and PSD-95 but their role remain to be elucidated (Pinatel and Faivre-Sarrailh, 2021). ...
Oligodendrocyte interactions with neurons fulfill distinct functions essential for cortical circuit maturation, albeit not completely understood. Through myelin formation, oligodendrocytes greatly increase speed and reliability of action potential propagation. This process requires high densities of voltage-gated sodium channels at nodes of Ranvier. Mechanisms underlying their assembly remain poorly understood. While evidences have attributed a key role to contacts between myelinating oligodendrocytes and the axon, our laboratory suggested that nodes of Ranvier formation may differ between neuronal subtypes. Oligodendrocyte secreted factors are indeed sufficient to cluster nodal proteins along hippocampal GABAergic axons prior to myelination, thereby forming node-like clusters or prenodes. Yet, the nature of the factors involved remained elusive. During my thesis, we identified the oligodendrocyte-derived clustering factors as a multimolecular complex, consisting of Contactin-1 combined with Phosphacan or Tenascin-R. To identify neuronal targets of oligodendrocytes, we investigated the influence of oligodendrocyte secreted factors on hippocampal GABAergic neuron physiology. Combination of electrophysiological and transcriptomic analyses suggested that oligodendrocyte secreted cues tend to reverse the observed changes in GABAergic neuron physiology caused by removing glial cells from cultures. Absence of glial cells decreases action potential discharge and excitatory events received by GABAergic neurons. Specific changes in transcripts for ion channels, transporters and synaptic markers were also induced and partly restored upon addition of oligodendrocyte secreted factors.
In vertebrates, oligodendrocytes (OLs) are glial cells of the central nervous system (CNS) responsible for the formation of the myelin sheath that surrounds the axons of neurons. The myelin sheath plays a crucial role in the transmission of neuronal information by promoting the rapid saltatory conduction of action potentials and providing neurons with structural and metabolic support. Saltatory conduction, first described in the peripheral nervous system (PNS), is now generally recognized as a universal evolutionary innovation to respond quickly to the environment: myelin helps us think and act fast. Nevertheless, the role of myelin in the central nervous system, especially in the brain, may not be primarily focused on accelerating conduction speed but rather on ensuring precision. Its principal function could be to coordinate various neuronal networks, promoting their synchronization through oscillations (or rhythms) relevant for specific information processing tasks. Interestingly, myelin has been directly involved in different types of cognitive processes relying on brain oscillations, and myelin plasticity is currently considered to be part of the fundamental mechanisms for memory formation and maintenance. However, despite ample evidence showing the involvement of myelin in cognition and neurodevelopmental disorders characterized by cognitive impairments, the link between myelin, brain oscillations, cognition and disease is not yet fully understood. In this review, we aim to highlight what is known and what remains to be explored to understand the role of myelin in high order brain processes.
