The complex organization of the Nodes of Ranvier is accomplished in part by myelinating Schwann cells in the peripheral nervous system PNS and oligodendrocytes in the central nervous system CNS. The clustering of Nav channels to the node is critically important for the rapid, saltatory propagation of action potentials.
Myelination divides the axonal membrane into distinct domains including nodes of Ranvier, paranodes, juxtaparanodes and internodes. The nodes of Ranvier are the sites of action potential repolarization and depolarization due to the clustering of high concentrations of ion channels, including Nav and Kv channels. The complement of Nav and Kv channels at the node are diverse and can include Nav1.
Kv channels at the node include Kv3. The paranode flanks the node of Ranvier and is the site where myelinating glial cells form septate-like junctions with the axonal membrane. Ankyrin-G has been shown to be highly enriched within oligodendrocytes on the glial side of the paranodal junction, whereas ankyrin-B is highly expressed at the Schwann cell paranodal membrane Chang et al. Glial ankyrins bind to the cell adhesion molecule NF at the paranodal junction and contribute to the assembly and maintenance of nodes of Ranvier in both the CNS and PNS.
The juxtaparanodes flank the paranodes and are enriched with dense populations of Kv channels known to module action potential conduction and help maintain internodal resting potential. Finally, the internodes make up the majority of the axon and are found underneath the myelin sheaths. Although the molecular composition between PNS and CNS nodes of Ranvier are similar, the mechanisms involved in their assembly are different mainly due to the glial cells types involved in myelination Figure 4.
In PNS node assembly, Nav channels are initially clustered at the edges of developing myelin sheaths, referred to as the heminodes, by the extracellular matrix ECM molecules gliomedin and neuronal cell adhesion molecule NrCAM from Schwann cell microvilli interacting with axonal NF Lambert et al.
Secondly, Nav channels are restricted to the nodal gap by the paranodal junction, which consists of glial-derived NF, found at paranodal region, in conjunction with Caspr and contactin within the axonal membrane.
The interaction between NF and the Caspr-contactin complex mediates Schwann cell interaction with the axon and formation of the paranodal junction. These paranodal junctions are thought to act as a restriction barrier during node of Ranvier assembly as the nodes are fully capable of forming in NrCAM and gliomedin knockout-mice, despite the fact that NF fails to localize to the heminodes of these mice Feinberg et al. In addition, the paranodal junction between myelinating Schwann cells of the PNS and oligodendrocytes in the CNS may function as a diffusion barrier to prevent the lateral movement of ion channels along the axonal plasma membrane Rasband et al.
In contrast, the significance of a diffusion barrier remains controversial since disturbing the paranodal junction only slightly perturbed Nav clustering Bhat et al. Interestingly, Amor et al. These findings suggest that the intact paranode can function as a secondary mechanism for Nav nodal clustering independent of axonal NF localization by glial-derived proteins.
In addition to gliomedin, other ECM proteins involved in heminode formation include syndecans, laminins, NG2 and versican, all of which also directly interact with NF Occhi et al. Nav and Kv channels bind with high affinity to the membrane-binding domain of ankyrin-G at the node via a CK2 phosphorylation-dependent mechanism as seen in the AIS Wang et al. Recent studies by Ho et al.
However, the ability of ankyrin-R to compensate for ankyrin-G at the node of Ranvier remains controversial Saifetiarova et al. Similar to the PNS, glial-derived extrinsic mechanisms contribute to CNS formation; however, in contrast to the microvilli of Schwann cells that make contact to the node in the PNS, the oligodendrocytes do not directly interact with the nodes in the CNS.
Three important components have been proposed to be important for node of Ranvier assembly in the CNS Figure 4. Secondly, the paranodal axo-glial complex forms, which consists of three main cell adhesion molecules: neurofascin kDa isoform NF derived from glial cells, and Caspr contactin-associated protein and contactin which are generated in the neuron. Lastly, the axonal scaffolding protein ankyrin-G is necessary to cluster and stabilize Nav channels to the node Gasser et al.
Nav channels were clustered at the node, likely due to the dramatic upregulation seen in the kDa isoform of ankyrin-G Jenkins et al. Ankyrin-G is referred to as the master organizer of the AIS; however, because the nodes require extrinsic regulation for their proper formation and function, the role of ankyrin-G as the master organizer of the node of Ranvier is less clear.
The fact that ankyrin-G contains binding sites for all known nodal components supports the theory that ankyrin-G is necessary and sufficient for node formation Hill et al.
In addition, mutation of the ankyrin-G-binding domain in NF inhibits its ability to cluster at the node Susuki et al. Zonta et al. Rescuing with NF is more intriguing as NF is not found at the node with ankyrin-G or Nav channels, but is still sufficient to rescue assembly of the node Zonta et al. Zhang et al. Future research should expand on these findings to better understand how deletion of ankyrin-G or neurofascin disrupts Nav clustering throughout CNS, and how this loss of Nav channels at the node impacts brain function.
While the pioneering work on the AIS and nodes of Ranvier done in cultured cells in vitro has given us great insights into the formation and function of these critical subcellular domains, recent work has highlighted the need to examine these mechanisms in vivo Komada and Soriano, ; Sherman et al.
Specific knockout animal models have elucidated how the AIS and nodes of Ranvier are formed in the intact organisms and have supported many of the findings from in vitro studies. Importantly, animal models also give us the ability to examine whether the mechanisms are conserved between cell types. For example, much of the work on the mechanisms of CNS node of Ranvier formation has been done in spinal cord or optic nerve. Are these mechanisms conserved in myelinated axons in the brain?
An increasing number of studies have shown that genetic mutations in components of both the AIS and nodes of Ranvier are involved in the pathophysiology of multiple diseases and injuries. As previously mentioned, ankyrin-G is absolutely essential to maintain the structural composition of the AIS and nodes of Ranvier and for normal axonal polarity.
Thus, mutations or loss-of-function of ANK3 might be expected to have a profound effect on neurological function. Consistent with this idea, genome-wide association studies have identified ANK3 as one of the most significant risk loci for bipolar disorder, and to a lesser degree schizophrenia Ferreira et al. A recent study by Lopez et al. Interestingly, mice lacking the exon 1b isoform loose Nav channel clustering at the AIS of PV interneurons and demonstrate behavioral characteristics of bipolar disorder, epilepsy and sudden death Lopez et al.
In addition, de novo missense mutations in ANK3 have been identified in autistic patients as well as severe cognitive deficits, borderline intelligence, severe attention deficit hyperactivity disorder ADHD and sleeping problems Awadalla et al.
The presence of a homozygous premature stop codon predicted to abolish the kDa isoform of ankyrin-G resulted in dramatic cognitive dysfunction and intellectual disability with IQ values below 50 Iqbal et al. It will be important to elucidate the precise effects of ANK3 mutations on neuronal function. SCN2A Nav1. In addition to mutations in sodium channel genes, loss-of-function mutations in both KCNQ2 and KCNQ3 potassium channel genes are linked to benign familial neonatal convulsions Singh et al.
Disruptions in spectrin cytoskeletal function and assembly have also been associated with neurological disease. The human spectrin family consists of two alpha- and five beta-spectrin subunits, which form heterodimers that assemble into tetramers through head-to-head and lateral associations Bennett and Lorenzo, Human dominant in-frame duplications and deletion mutations in SPTAN1 have been found in patients with early-onset epileptic encephalopathies, hypomyelination, intellectual disability and blindness starting in children under age 3 Saitsu et al.
Increasing evidence also suggests degeneration of the axon is an important component underlying multiple sclerosis MS pathology; however, the mechanisms that contribute to axonal loss remain elusive Dutta and Trapp, Patients suffering from MS demonstrated changes in expression and localization of Nav channels and neurofascin, as well as the paranodal protein Caspr Wolswijk and Balesar, ; Craner et al.
One potential mechanism that contributes to MS may be abnormal axo-glial interaction at the paranode, which would be expected to disrupt axonal transport and alter normal organization of myelinated axons Sousa and Bhat, Mathey et al. In addition to the nodes of Ranvier, the effect of demyelination on the AIS may be another potential mechanism that contributes to MS. Hamada and Kole showed that demyelinating axons using cuprizone caused the AIS to shift more proximal to the soma and reduced action potential initiation.
Consistent with these findings, Clark et al. Ultimately, the AIS is a primary target during inflammation and, in addition to demyelination of the distal axon, may contribute to inflammatory demyelinating diseases such as MS. In a rat model of mild traumatic brain injury, Baalman et al.
These changes in the AIS perhaps highlight a potential mechanism underlying mild traumatic brain injury and future studies will be important to elucidate the specific molecular components that contribute to the structural and functional changes in the AIS.
Overall, changes in excitable domains of the axon or their constituent proteins have profound impact on neurological function. Although many of the proteins of the AIS and nodes of Ranvier have important functions in other cellular domains, the overlapping phenotypes seen with loss of function of different AIS and nodal components suggest that dysfunction of these axonal membrane domains is a major factor in the development of disease.
As we increasingly understand the genetic basis of neurological disorders, we will likely uncover more genes involved in the formation and function of axonal domains that can give us more insight into the etiology of human disease. The structural assembly and maintenance of the axon relies on the precise organization between ankyrins, spectrins, membrane-associated proteins and actin and microtubule cytoskeletal proteins.
The mechanisms underlying the interaction between these components at the AISs and nodes of Ranvier are now becoming more apparent. A better understanding of the organization and maintenance of axonal excitable domains as well as how abnormalities in their signaling may lead to altered axonal function will provide insight to novel therapeutic targets for the treatment of human diseases of the nervous system. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
We would also like to thank Dr. Al-Bassam, S. Differential trafficking of transport vesicles contributes to the localization of dendritic proteins. Cell Rep. Amor, V. Elife 6:e Ango, F. Ankyrin-based subcellular gradient of neurofascin, an immunoglobulin family protein, directs GABAergic innervation at Purkinje axon initial segment. Cell , — Awadalla, P. Direct measure of the de novo mutation rate in autism and schizophrenia cohorts. Baalman, K. Blast wave exposure impairs memory and decreases axon initial segment length.
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Neuropsychopharmacology 34, — Czogalla, A. Life Sci. Davis, J. Davis, L. STED nanoscopy reveals the ubiquity of subcortical cytoskeleton periodicity in living neurons. Dotti, C. Ion channels are remarkable proteins, present in the lipid bilayer membrane of both animal and plant cells and their organelles, such as nucleus, endoplasmic reticulum, Golgi apparatus, mitochondria, chloroplasts, and lysosomes.
Scientists have been working on these amazing transmembrane proteins since the beginning of the last century, which has resulted in three sets of Nobel prizes in , , and Sir John Carew Eccles, Alan Lloyd Hodgkin, and Andrew Fielding Huxley in received Nobel Prize for Physiology and Medicine for their discoveries concerning the ionic mechanisms involved in excitation and inhibition in the peripheral and central portions of the nerve cell membrane [ 1 , 2 ]. Similarly, Erwin Neher and Bert Sakmann in proved that cell membranes have individual ion channels through which tiny currents can pass, which are big enough to generate communications between pre- and postsynaptic neurons by converting chemical or mechanical events into electrical signals [ 3 , 4 ].
The Nobel Prize in Chemistry for was shared between two scientists Agre [ 5 ] and Roderick MacKinnon [ 6 ] who have made fundamental discoveries concerning how water and ions move through cell membranes.
In this book, we have nine very diverse and informative chapters including this introductory chapter on the importance of both cations and anions passing through these ion channels. First chapter is the introductory chapter which briefly overview the other eight chapters included in this book, as well as discusses the diversity and classification of ion channels, nature and number of gating for these ion channels along with shedding some light on Channellopathies.
Second chapter deals with the voltage-gated sodium channels in drug discovery. Sodium channels are the very first one to be discovered when Hodgkin and Katz were performing their experiments on squid axons showing that there would be no action potential if sodium ions are not present in the extracellular fluid.
In this chapter, genetic evolution and subtype distribution of this super family of voltage-gated sodium Nav channels are introduced, and there is a discussion about how the changes in the structure alter their functions.
Third chapter argues the modulation of Nav by small and large molecules, along with the discussion on the major challenges for the Nav-targeted drug discoveries. Fourth chapter is taking us to a striking journey about how the genetic mutations bring change in their product proteins and resultant disorders such as Dravet syndrome. SCN1A gene is responsible for this condition and there is a word of caution for the medical practitioners to not prescribe sodium channel blockers for the epileptic patients with this mutation, as the medicine will aggravate their condition.
Fifth chapter is about potassium channels: there are many different types of the potassium channels many more than sodium ion channels. In this chapter, authors have discussed the role of two gap junction proteins—connexins and pannexins—in maintaining the homeostasis of potassium ions, taking cochlea as an example. Authors developed a novel method for the early detection of the genetic mutations for the inner ear impairment. Sixth chapter is dealing with the structure and function of L-type calcium channels and how voltage-gated calcium channels VGCCs manage the electrical signaling of cells by allowing the selective-diffusion of calcium ions in response to the changes in the cellular membrane potential.
Among the different VGCCs, the long-lasting or the L-type calcium channels LTCCs are prevalently expressed in a variety of cells, such as skeletal muscles, ventricular myocytes, smooth muscles, and dendritic cells and form the largest family of the VGCCs.
Their wide expression pattern and significant role in diverse cellular events have made these channels the major targets for drug development. Seventh chapter is about the regulation of pain through calcium channels. In this chapter, authors present a large body of clinical, biochemical, biophysical, pharmacological, and genetic evidences pointing toward calcium-permeable channels as the key players in pain conditions.
The primary goal of this chapter is to present an overview of the different classes of calcium-permeable channels and how they change to modulate the sensation of pain in acute and chronic states. They are a group of transmembrane ion channels that open or close in response to the binding of a chemical messenger ligand , such as a neurotransmitter.
Voltage-gated ion channels, also known as voltage-dependent ion channels, are channels whose permeability is influenced by the membrane potential. They form another very large group, with each member having a particular ion selectivity and a particular voltage dependence. Many are also time-dependent—in other words, they do not respond immediately to a voltage change, but only after a delay.
Voltage-gated channels are essential for the generation and propagation of action potentials. Such ion pumps take in ions from one side of the membrane decreasing its concentration there and release them on the other side increasing its concentration there.
Ion pump example : Example of primary active transport, where energy from hydrolysis of ATP is directly coupled to the movement of a specific substance across a membrane independent of any other species. The potential difference in a resting neuron is called the resting membrane potential. This causes the membrane to be polarized. The resting membrane potential exists only across the membrane.
Most of the time, the difference in ionic composition of the intracellular and extracellular fluids and difference in ion permeability generates the resting membrane potential difference. The interactions that generate the resting potential are modeled by the Goldman equation. It is based on the charges of the ions in question, as well as the difference between their inside and outside concentrations and the relative permeability of the plasma membrane to each ion where:.
Goldman equation: R is the universal gas constant, equal to 8. The Goldman formula essentially expresses the membrane potential as an average of the reversal potentials for the individual ion types, weighted by permeability. In most animal cells, the permeability to potassium is much higher in the resting state than the permeability to sodium.
Consequently, the resting potential is usually close to the potassium reversal potential. The membrane potential allows a cell to function as a battery, providing electrical power to activities within the cell and between cells. In neurons, a sufficiently large depolarization can evoke an action potential in which the membrane potential changes rapidly.
Membrane potential also transmembrane potential or membrane voltage is the difference in electrical potential between the interior and the exterior of a biological cell. All animal cells are surrounded by a plasma membrane composed of a lipid bilayer embedded with various protein types.
The membrane serves as both an insulator and a semi-permeable diffusion barrier to the movement of ions. Ions are moved across the cell membrane either through active using energy or passive not using energy transport. Virtually all eukaryotic cells including cells from animals, plants, and fungi maintain a nonzero transmembrane potential, usually with a negative voltage in the cell interior compared to the cell exterior.
The membrane potential has two basic functions. Second, in electrically excitable cells such as neurons and muscle cells, it is used for transmitting signals between different parts of a cell. Signals are generated by opening or closing of ion channels at one point in the membrane, producing a local change in the membrane potential that causes electric current to flow rapidly to other points in the membrane.
In non-excitable cells, and in excitable cells in their baseline states, the membrane potential is held at a relatively stable value called the resting potential. For neurons, typical values of the resting potential range from —70 to —80 millivolts; that is, the interior of a cell has a negative baseline voltage of a bit less than one tenth of a volt.
The opening and closing of ion channels can induce a departure from the resting potential. This is called a depolarization if the interior voltage becomes more positive say from —70 mV to —60 mV , or a hyperpolarization if the interior voltage becomes more negative say from —70 mV to —80 mV. The changes in membrane potential can be small or larger graded potentials depending on how many ion channels are activated and what type they are.
In excitable cells, a sufficiently large depolarization can evoke an action potential in which the membrane potential changes rapidly and significantly for a short time on the order of 1 to milliseconds , often reversing its polarity. Action potentials are generated by the activation of certain voltage-gated ion channels.
Action potential : A. Schematic and B. The action potential is a clear example of how changes in membrane potential can act as a signal. Neurons typically send signals over long distances by generating and propagating action potentials over excitable axonal membrane.
When the membrane potential of the axon hillock of a neuron reaches threshold, a rapid change in membrane potential occurs in the form of an action potential. This moving change in membrane potential has three phases. First is depolarization, followed by repolarization and a short period of hyperpolarization. These three events happen over just a few milliseconds.
The propagation of action potential is independent of stimulus strength but dependent on refractory periods. The period from the opening of the sodium channels until the sodium channels begin to reset is called the absolute refractory period. During this period, the neuron cannot respond to another stimulus, no matter how strong.
A synapse is a structural junction that mediates information transfer from one neuron to the next or from one neuron to an effector cell as in muscle or gland. In the nervous system, a synapse is a structure that permits the axon of a neuron to pass an electrical or chemical signal the axon of another neuron or to another cell type. The neuron conducting impulses towards the synapse is called pre-synaptic neuron. The neuron transmitting the electrical impulse away from the synapse is called post-synaptic neuron, if the post-synaptic cell is not neuronal it is sometimes referred to as an effector cell.
Synapses can be classified by the type of cellular structures serving as the pre- and post-synaptic components. The vast majority of synapses in the mammalian nervous system are axo-axonal axon synapsing with another axon or axo-dendritic synapses axon synapsing upon a dendrite. However, a variety of other arrangements exist. Neurotransmitters are stored in synaptic vesicles within the pre-synaptic neuron 2.
In a chemical synapse, the plasma membrane of the pre-synaptic neuron is closely associated with the plasma membrane of the post-synaptic cell, with the gap between termed the synaptic cleft. The synapse is stabilized by the expression of synaptic adhesion molecules projecting from both the pre- and post-synaptic cells maintaining the close association.
Upon arrival of an action potential at the pre-synaptic axon neurotransmitters are released into the synaptic cleft via the action of voltage-gated calcium channels. This neurotransmitter binds to receptors located in the plasma membrane of the post-synaptic cell which can elicit an electrical response or the activation of a secondary messenger pathway.
Because of the complexity of receptor signal transduction, chemical synapses can have complex effects on the post-synaptic cell, and are able to induce effects such as gain, or amplification, whereby the strength of the signal is increased in the post-synaptic cell.
In an electrical synapse, the pre-synaptic and post-synaptic cell membranes are fused and connected by special channels called gap junctions that are capable of passing electrical current. These gap junctions contain connexion proteins which allow ions and small molecules to flow directly from one neuron to the next.
The neurons are electrically coupled and transmission across these synapses is very rapid, allowing for faster signal processing than chemical synapses. However, due to their nature electical synapses cannot induce gain of signal strength. Electrical Synapse : The membranes of pre and post-synaptic cells are fused and punctured by gap-junctions.
When open they allow the rapid diffusion of ions across the plasma membranes allowing for rapid, continuous signal processing across the synapse. Postsynaptic potentials are excitatory or inhibitory changes in the graded membrane potential in the postsynaptic terminal of a chemical synapse.
Postsynaptic potentials are changes in the membrane potential of the postsynaptic terminal of a chemical synapse. Postsynaptic potentials are graded potentials and should not be confused with action potentials, although their function is to initiate or inhibit action potentials.
Many postsynaptic membrane receptors at chemical synapses are specialized to open ion channels. This converts a chemical signal into an electrical signal. Chemical synapses are either excitatory or inhibitory depending on how they affect the membrane potential of the postsynaptic neuron. The neurotransmitters bind to receptors on the postsynaptic terminal resulting in an opening of ion channels. Functional synaptic architecture of callosal inputs in mouse primary visual cortex.
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