Do voltage-gated channels in a neuron use ATP

Do voltage-gated channels in a neuron use ATP

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I have a question about action potentials in a neuron.

Do voltage-gated sodium and potassium channels use ATP? I mean when they are closed or when they want to open the gate, do they use ATP?

No, they change conformation in response to voltage. Wikipedia has some general discussion of the gating process, as would any basic neuroscience textbook.

The primary energy (ATP) cost of neurotransmission is in establishing ion concentration gradients, via the sodium/potassium ATPase. You can think of this as a special case of secondary active transport, where the energy costs are in establishing a gradient that is then used for a later process which does not cost any direct energy.

Structure and function of voltage-gated sodium channels

Sodium channels mediate fast depolarization and conduct electrical impulses throughout nerve, muscle and heart. This paper reviews the links between sodium channel structure and function.

Sodium channels have a modular architecture, with distinct regions for the pore and the gates. The separation is far from absolute, however, with extensive interaction among the various parts of the channel.

At a molecular level, sodium channels are not static: they move extensively in the course of gating and ion translocation.

Sodium channels bind local anaesthetics and various toxins. In some cases, the relevant sites have been partially identified.

Sodium channels are subject to regulation at the levels of transcription, subunit interaction and post-translational modification (notably glycosylation and phosphorylation).

Sodium channels play a central role in physiology: they transmit depolarizing impulses rapidly throughout cells and cell networks, thereby enabling co-ordination of higher processes ranging from locomotion to cognition. These channels are also of special importance for the history of physiology. Elucidation of their fundamental properties in the squid axon launched modern channel theory. In particular, the work of Hodgkin and Huxley on sodium channels, published in this Journal, revolutionized electrophysiology by elegantly dissecting the elementary processes of gating and permeation (Hodgkin & Huxley, 1952). More recently, sodium channels were the first voltage-dependent ion channels to be cloned (Noda et al. 1984), ushering in the era of heterologous expression and molecular manipulation. The cloning happily coincided with the development of patch-clamp techniques, which enabled single-channel recordings. This paper reviews the general concepts of sodium channel structure and function that have emerged over the past half-century. Because the goal of this series is to be brief, citations to the literature are selective. The reader is referred to other reviews (e.g. Fozzard & Hanck, 1996) for more encyclopaedic treatments.

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Neuromuscular Junction (NMJ): A Target for Natural and Environmental Toxins in Humans

Calcium Channels

The voltage-gated calcium channels are major signaling transducers, converting the depolarization of a cell membrane into the influx of Ca 2+ . The structural organization of the voltage-gated Ca 2+ channel is virtually identical to that of the voltage-gated sodium channel, comprising an α subunit, which contains those structures that form the ion channel and the signaling domains, and one or more auxiliary subunits. As in the sodium channel, the α subunit of the calcium channel is composed of four domains, each containing six hydrophobic sequences, the pore being formed when the four domains form a pseudo-symmetrical array across the cell membrane. The known voltage-gated calcium channels fall into one of three major types, defined by their role. CaV1 voltage-gated calcium channels, also known as type L, are involved in the activation of intracellular signaling processes, including gene regulation, endocrine secretion, and the contraction of smooth, cardiac, and skeletal muscle. CaV2, also known as types N, P/Q, and R channels, regulate fast synaptic transmission in the nervous system CaV3, also known as T-type channels, are primarily involved with the regulation of repetitive firing in the nervous system. There is a great deal of diversity of function within the individual types of voltage-gated calcium ion channels because there are at least ten recognizable isoforms of the α subunit, further complicated by extensive alternative splicing. A similar diversity among the auxiliary units gives rise to a high degree of combinatorial heterogeneity.

Natural toxins targeting voltage-gated calcium channels are produced by large numbers of predatory animals. The toxins involved include the ω-conotoxins, toxins from the venoms of spiders of the genera Agenelopsis, Grammostola, Hololena, and Plectreurys and of snakes of the genera Dendroaspis. The ω-toxins of Conus (i.e., the ω-conotoxins) and Agelenopsis (i.e., the ω-agatoxins) are by far the most widely used toxins in calcium channel pharmacology. Despite the very high specificity of the ω-conotoxins and-agatoxins for voltage-gated calcium channels, they are structurally unrelated. The ω-conotoxins are small polypeptides of 24–30 residues cross-linked by three disulfide bonds the ω-agatoxins are small polypeptides of 45–75 residues cross-linked by four disulfide bonds. With care, the pharmacological differentiation between the various types of calcium channel may be made on the basis of sensitivity to a small number of agents. L-type channels are very sensitive to the dihydropyridines and are resistant to the majority of ω-conotoxins and-agatoxins. P/Q channels are particularly sensitive to ω-conotoxin MV11C and ω-agatoxin 1VA, and N channels are particularly sensitive to ω-conotoxin GV1A. This approach to the classification of calcium channels is, however, fraught with difficulty, especially when a novel calcium channel is being classified, because the majority of ω-toxins are selective for voltage-gated calcium channels but are not particularly specific for an individual channel type.

Other toxins directly affecting voltage-gated calcium channels include ω-grammotoxin SIA, isolated from the venom of the Chilean tarantula Grammostola spatulata, which blocks N-, P-, and Q-type channels but not L-type hololena toxin from the venom of the spider Hololena curta and PLTX11 from the venom of the spider Plectreurus tristes, which block voltage-gated calcium channels in insects. Calciseptine, isolated from the venom of the mamba Dendroaspis polylepis, inhibits L-type Ca 2+ channels in the aorta, ventricular muscle, and dorsal root ganglia calcicludine, from the venom of Dendroaspis augusticeps, blocks L-, N-, and P-type channels in the CNS. The typical response to the blockade of voltage-gated calcium channels at the NMJ is the failure of evoked transmission and the packing of the nerve terminal with synaptic vesicles.

Concluding Remarks

Malignant tumors constitute a serious threat to human health. With the deepening of interdisciplinary research in molecular biology, cell biology, and pharmacology, the research on the relationship between ion channels and tumors has made great progress. It has been elucidated that VGSCs can be expressed in invasive cancer cells and can increase the ability of tumor cells to move and invade. Therefore, they can be considered to be important regulators of cancer development. However, the expression of the α and β subunits of VGSCs in different tumors and their role in disease progression need to be further investigated. In addition, the molecular mechanisms involved in the regulation of VGSCs activity are still unclear. Some of the channel blockers currently being developed may act as an intervention for metastatic disease. This will facilitate the use of VGSCs as a diagnostic marker for early diagnosis and as a therapeutic target in the treatment of clinical metastatic tumor diseases.

Ions enter cells via cell membrane through ion channels that are gated channels or non gated ion channels. Voltage gated and ligand gated ion channels are two types that respond to a voltage difference and ligand binding respectively. Voltage gated ion channels are ion specific while ligand gated ion channels are not selective. The below infographic presents the difference between voltage gated and ligand gated ion channels in tabular form.

Chemical and Electrical Synapses

The synapse or “gap” is the place where information is transmitted from one neuron to another. Synapses usually form between axon terminals and dendritic spines, but this is not universally true. There are also axon-to-axon, dendrite-to-dendrite, and axon-to-cell body synapses. The neuron transmitting the signal is called the presynaptic neuron, and the neuron receiving the signal is called the postsynaptic neuron. Note that these designations are relative to a particular synapse—most neurons are both presynaptic and postsynaptic. There are two types of synapses: chemical and electrical.

Chemical Synapse

Figure 6. This pseudocolored image taken with a scanning electron microscope shows an axon terminal that was broken open to reveal synaptic vesicles (blue and orange) inside the neuron. (credit: modification of work by Tina Carvalho, NIH-NIGMS scale-bar data from Matt Russell)

When an action potential reaches the axon terminal it depolarizes the membrane and opens voltage-gated Na + channels. Na + ions enter the cell, further depolarizing the presynaptic membrane. This depolarization causes voltage-gated Ca 2+ channels to open. Calcium ions entering the cell initiate a signaling cascade that causes small membrane-bound vesicles, called synaptic vesicles, containing neurotransmitter molecules to fuse with the presynaptic membrane. Synaptic vesicles are shown in Figure 6, which is an image from a scanning electron microscope.

Fusion of a vesicle with the presynaptic membrane causes neurotransmitter to be released into the synaptic cleft, the extracellular space between the presynaptic and postsynaptic membranes, as illustrated in Figure 7. The neurotransmitter diffuses across the synaptic cleft and binds to receptor proteins on the postsynaptic membrane.

Figure 7. Communication at chemical synapses requires release of neurotransmitters. When the presynaptic membrane is depolarized, voltage-gated Ca2 + channels open and allow Ca2 + to enter the cell. The calcium entry causes synaptic vesicles to fuse with the membrane and release neurotransmitter molecules into the synaptic cleft. The neurotransmitter diffuses across the synaptic cleft and binds to ligand-gated ion channels in the postsynaptic membrane, resulting in a localized depolarization or hyperpolarization of the postsynaptic neuron.

The binding of a specific neurotransmitter causes particular ion channels, in this case ligand-gated channels, on the postsynaptic membrane to open. Neurotransmitters can either have excitatory or inhibitory effects on the postsynaptic membrane. There are several examples of well known neurotransmitters detailed in Table 1. For example, when acetylcholine is released at the synapse between a nerve and muscle (called the neuromuscular junction) by a presynaptic neuron, it causes postsynaptic Na + channels to open. Na + enters the postsynaptic cell and causes the postsynaptic membrane to depolarize. This depolarization is called an excitatory postsynaptic potential (EPSP) and makes the postsynaptic neuron more likely to fire an action potential. Release of neurotransmitter at inhibitory synapses causes inhibitory postsynaptic potentials (IPSPs), a hyperpolarization of the presynaptic membrane. For example, when the neurotransmitter GABA (gamma-aminobutyric acid) is released from a presynaptic neuron, it binds to and opens Cl – channels. Cl – ions enter the cell and hyperpolarizes the membrane, making the neuron less likely to fire an action potential.

Once neurotransmission has occurred, the neurotransmitter must be removed from the synaptic cleft so the postsynaptic membrane can “reset” and be ready to receive another signal. This can be accomplished in three ways: the neurotransmitter can diffuse away from the synaptic cleft, it can be degraded by enzymes in the synaptic cleft, or it can be recycled (sometimes called reuptake) by the presynaptic neuron. Several drugs act at this step of neurotransmission. For example, some drugs that are given to Alzheimer’s patients work by inhibiting acetylcholinesterase, the enzyme that degrades acetylcholine. This inhibition of the enzyme essentially increases neurotransmission at synapses that release acetylcholine. Once released, the acetylcholine stays in the cleft and can continually bind and unbind to postsynaptic receptors.

Table 1. Neurotransmitters
Neurotransmitter Function Location
Acetylcholine muscle control, memory CNS and/or PNS
Serotonin intestinal movement, mood regulation, sleep gut, CNS
Dopamine voluntary muscle movements, cognition, reward pathways hypothalamus
Norepinephrine fight or flight response adrenal medulla
GABA inhibits CNS brain
Glutamate generally an excitatory neurotransmitter, memory CNS, PNS

Electrical Synapse

While electrical synapses are fewer in number than chemical synapses, they are found in all nervous systems and play important and unique roles. The mode of neurotransmission in electrical synapses is quite different from that in chemical synapses. In an electrical synapse, the presynaptic and postsynaptic membranes are very close together and are actually physically connected by channel proteins forming gap junctions. Gap junctions allow current to pass directly from one cell to the next. In addition to the ions that carry this current, other molecules, such as ATP, can diffuse through the large gap junction pores.

There are key differences between chemical and electrical synapses. Because chemical synapses depend on the release of neurotransmitter molecules from synaptic vesicles to pass on their signal, there is an approximately one millisecond delay between when the axon potential reaches the presynaptic terminal and when the neurotransmitter leads to opening of postsynaptic ion channels. Additionally, this signaling is unidirectional. Signaling in electrical synapses, in contrast, is virtually instantaneous (which is important for synapses involved in key reflexes), and some electrical synapses are bidirectional. Electrical synapses are also more reliable as they are less likely to be blocked, and they are important for synchronizing the electrical activity of a group of neurons. For example, electrical synapses in the thalamus are thought to regulate slow-wave sleep, and disruption of these synapses can cause seizures.

Types of Ion Channels

Ion channels can be classified by how they respond to their environment. For example, ion channels can be voltage-sensitive in that they open and close in response to the voltage across the membrane. Ligand-gated channels form another important class these ion channels open and close in response to the binding of a ligand molecule such as a neurotransmitter. Other ion channels open and close with mechanical forces. Still others, such as those of sensory neurons, open and close in response to other stimuli, such as light, temperature, or pressure. The most common types of ion channels are described below.

Crash Course Nervous System 2: How Action Potentials Work

Post 2 in the Crash Course series on how the nervous system works: Action Potential!

Neurons are extraordinary cells. Beyond being intricately branched and gigantic relative to most cells, every second hundreds of billions of electrical impulses called action potentials are transmitted in your body. Before we check out how that works, it’s useful to refresh a few electricity terms.

Voltage is a difference in electrical charge. In neurons, voltage is measured in milivolts (1/1000th of a volt) and is called membrane potential. The greater the charge difference, the greater the membrane potential. Current is the flow of electricity. In neurons, currents refer to the flow of positive or negative ions across cell membranes. But before we get to the flow of current, let’s understand the default or “resting state” of a neuron:

Neuron Resting Potential via Crash Course

Your body is separated from the outside world by skin. This allows the internal state of your body to have different conditions than the outside world. Neurons have their own “skin” in the form of a cell membrane. It has ion gates – macromolecules made of many proteins – that change shape when specific molecules are present, allowing other specific ions (charged particles) to pass through the cell membrane. The movement of these ions changes the charge of the cell, causing a cascade of activity.

When neurons are at rest and not receiving electrical signal. their internal charge is negative thanks to the activity of a remarkable macromolecular machine: the sodium-potassium pump. This trans-membrane protein actively pumps sodium ions across their concentration gradient to the outside of the cell.

Sodium potassium pump maintains an electrochemical gradient inside neurons (shown in teal). The purple molecule at bottom right is ATP, providing energy to activate the pump. For every two positively charged potassium ions (blue) it pumps in, it pumps out three positively charged potassium ions (red), making it more positively charged outside the neuron. Via Crash Course

In addition to sodium potassium pumps, neurons have many types of ion channels.

Ion channels allow many charged ions to pass across a cell membrane. As charged particles rapidly diffuse across the membrane, they depolarize it, thus changing its charge.

Here are a few different types of ion gates:

The most common ion channels are voltage gated. They open at certain membrane potential thresholds. Via crash course

Other ion channels include Ligand gates (red), activated by neurotransmitters such as acetylcholine, and Mechanical gates (yellow), activated by physical stretching. via Crash Course

How an Action Potential Works

When all these gates are closed, a neuron is at rest. It’s polarized with a static membrane potential voltage of -70 mV .

Resting state membrane potential via Crash Course

But say a stimuli hits a neuron, triggering an ion channel to open. As ions pass into the cell (much faster than shown below), they alter the membrane’s charge. Watch the white line to the right. It rises as voltage approaches a very important threshold: -55 mV.

It’s all about getting to -55 mV. Sodium ions (red) enter neuron. Via Crash Course

Why -55 mV? At this threshold, thousands of voltage gated sodium channels open. A flood of positively charged sodium ions enter the cell and it becomes rapidly positively charged or depolarized. But this change in charge won’t last long.

Sodium gates (purple) let forth a flood of positive sodium ions (red) into the neuron, resulting in depolarization. Via Crash Course

As a neuron reaches an internal charge of around +30 mV, a conformational shape change happens in the sodium channels. They close and voltage gated potassium channels open, allowing positively charged potassium ions to leave the cell.

Membrane repolarization. Sodium channels (light purple) close. Potassium channels (dark purple) open and diffuse positively charged ions out of the cell. via Crash Course

This drops the internal charge of the neuron briefly below its resting state of -70 mV, activating the sodium potassium pumps to finish the job and bring the neuron to a maintained homeostasis. The entire process lasts 1-2 ms (1/1000th of a second).

Action potential moves through a neuron branch. Via Crash Course

In this manner, action potentials propagate down neuron branches as chain reactions, causing a wave of depolarizations and repolarizations. Action potentials only travel in one direction.

So an action potential is moving along a branch when suddenly it reaches the end, the point of no return: a synapse.

A number of things can happen when an action potential reaches a synapse. To keep it simple, let’s consider the case of a chemical synapse, the type of junction that uses neurotransmitters.

Action potentials here activate local voltage gated calcium channels, releasing a flow of positive ions into the cell. The calcium causes sack like structures full of neurotransmitters called vesicles to release their contents into the synaptic cleft, the area between two neurons.

An action potential reaches the end of the line: a chemical synapse. Via Crash Course

Neurotransmitters are released from vesicles into the synaptic cleft, a region less than five millionths of a centimeter wide. They bind to receptor sites on the postsynaptic cell, triggering either excitation or inhibition. Via Crash Course

There are many types of neurotransmitters. Some are excitatory others are inhibitory.

Here’s how excitatory and inhibitory neurotransmitters differ when it comes to the electrodynamics of neurons (see post 1 for a refresher on membrane potential). All images by Crash Course:

Inhibitory neurotransmitters push neurons farther away from their threshold for having an action potential (hyperpolarization), making it harder for them to fire. Via Crash Course Excitatory neurotransmitters bring neurons closer to their threshold for having an action potential (depolarizing them), making it easier for them to fire. Via Crash Course

It’s neither a single synapse nor a single neurotransmitter that matters. There are over one hundred different types of neurotransmitters and over 100 trillion synapses in your brain. A single neuron can have thousands or even tens of thousands of synapses. As Hank Green points out in this video, “the likelihood of a postsynaptic neuron developing an action potential depends on the sum of the excitation and inhibition in an area.” This is commonly called constructive signal summation and is illustrated by EyeWire’s first scientific discovery (Nature 2014).

A few more Action Potential Factoids

Immediately following an action potential, neurons have a refractory period, a brief bit of time where they are not responsive to further stimuli. If another stimuli reaches a neuron during this period, it will not cause an action potential, no matter how strong the incoming signal is. This results in action potentials only propagating in one direction.

Neurons have consistent voltage thresholds: -55 mV activation,

+30 mV repolarization. They vary their signals then not by Voltage (amplitude) but by frequency and speed (conduction velocity).

Weaker stimuli tend to produce slower, lower frequency signals while stronger or more intense stimuli tend to produce more rapid, higher frequency signals.

Myelinated (insulated) neurons, such as are found in white matter and the peripheral nervous system, send the fastest signals.

Myelinated action potential travels oh so fast because it effectively “leaps” from one myelin gap (nodes of ranvier) to the next. Via Crash Course

In the central nervous system, Myelin is produced by cells called Oligodendrocytes, which wrap around axons.

Oligodendrocyte merrily making myelin sheaths. Via Crash Course

Thanks for reading. Be sure to subscribe to Crash Course on YouTube and let us know what you think about this post in EyeWire chat. For science!

Watch the video: ΤΗΣ ΚΑΚΟΜΟΙΡΑΣ! Γιαννακόπουλος: Κλείστε τον Παπανδρέου στη ντουλάπα! Αυτός u0026 ο Σημίτης είναι (October 2022).