Ion channels and gradients
Ion channels are membrane proteins that facilitate and regulate the movement of ions, such as Na+, K+, Ca2+ and Cl- through the cell membrane. These channels play a key role in essential cell functions including generation of action potentials and graded membrane potentials in neurons as well as synaptic communication between neurons.
All cells display a potential difference (voltage) across their membrane. The cell membrane serves as a barrier separating the intracellular from the extracellular compartment, each characterized by distinct compositions of solutes and ions. For example, the intracellular fluid is primarily enriched with negatively charged proteins and K+ ions, while Na+, Cl- and Ca2+ ions are predominantly found in the extracellular fluid. This uneven ion distribution is supported by carriers like Na+/K+ ATPase and creates a potential difference across the cell membrane (polarized membrane). Normal neuronal resting potential is around -70mV. Under certain conditions, the potential difference across the cell membrane can be increased (hyperpolarization) or decreased (depolarization).
The electrochemical gradient of ions across the cell membrane would naturally lead to the movement of ions from one side to the other until a balance in concentration and electric charge is achieved. However, this expected process does not occur due to the unique structure of the cell membrane, which is composed of a phospholipid bilayer, along with proteins and sugars that extend within or across the layers. This bilayer is hydrophobic on the inside and hydrophilic on the outside. Ions, on the other hand, are highly hydrophilic, surrounded by water molecules. As a result, the transfer of ions through the phospholipid bilayer is energetically unfavorable and can only take place through specialized ion channels.
|Ion channels are transmembrane proteins of the cell membrane, assembled by subunits that form a pore and accessory structures.
- Facilitation of ion passage through the cell membrane.
- Selectivity in ion movement across the cell membrane.
- Activation and deactivation of ion passage via alterations in protein structure triggered by a stimulus.
- Ligand-gated ion channels are stimulated by chemical substances.
- Voltage-gated ion channels are stimulated by alterations of the potential difference across the cell membrane.
- Phosphorylation-gated ion channels change their structure and permeability by phosphorylation.
- Mechanical-gated ion channels respond to mechanical forces.
- Leakage ion channels are constantly activated.
- Ion selectivity
- Ion channel gating
- Types of ion channels
- Clinical relations
Ion channels are proteins that span across the cell membrane and are firmly inserted into the phospholipid bilayer (transmembrane proteins). They are made up from transmembrane subunits that assemble to form a pore and accessory structures. The number of these subunits varies across different subfamilies of ion channels.
Ion channels fulfill three main functions:
- Facilitation of ion transport: Due to its structure and properties, the phospholipid bilayer actively inhibits the passage of charged molecules across the cell membrane. Ion channels enable ions to pass through them passively, without energy consumption. When the pore is open, ions can diffuse down their respective electrochemical gradients, reaching an astonishing rate of 10 million ions per second.
- Selectivity: The majority of the ion channels are highly selective, allowing only specific ions to traverse through them.
- Activation in response to stimuli: Due to their unique protein structure, ion channels maintain a closed state, preventing ions from passing through. However, in response to various stimuli, which can be of electrical, chemical or mechanical nature, the structure of the channel can change, leading to the opening of the pore, allowing ions to pass. An exception to this pattern of activation/deactivation are the leakage ion channels that are constantly activated and thus remain in an open state.
The movement of ions through their respective channels occurs without energy consumption. It is solely driven by the electrochemical gradient, which dictates the net flow of ions across the cell membrane. A fundamental question, however, is how ion channels achieve selectivity, allowing only specific ions to pass through. The prevailing theory on the mechanisms underlying this selectivity points to a combination of factors which include ion size, electrical charge and interaction with the channel's structure:
- Role of ion size and electrical charge: Ions vary in size and electrical charge, attracting different numbers of water molecules around them (hydration shell). For instance, Na+ is smaller than K+ and carries a greater electrical charge due to its reduced size. Consequently, each Na+ ion is surrounded by more water molecules, forming a larger hydration shell compared to K+.
- Pore size limitation: The ion channel pore is too small to accommodate ions surrounded by a hydration shell of water molecules. Therefore, ions must discard these water molecules to pass through the pore, a process demanding a substantial amount of energy.
- Electrical charge of the pore: The lining of the pore is charged, which allows for a selective passage of anions or cations, respectively.
In the case of Na+ channels, specific regions inside the pore contain amino acids, such as aspartic and glutamic acid, carrying a negative electric charge sufficient to attract Na+ ions. This attraction provides the ions with the necessary energy to discard some of their surrounding water molecules, reducing their size to a point where they can effectively diffuse down their electrochemical gradient and pass through the channel's pore. Given its larger diameter, K+ cannot approach these negatively charged regions of the pore close enough to benefit from this energy-boosting mechanism, making it ineffective for K+ to traverse Na+ channels.
Conversely, the pores of K+ channels have regions with carbonyl and hydroxyl oxygen atoms featuring a weaker electrical field. In these regions, K+ ions can interact and release the surrounding water molecules, enabling K+ ions to pass through the channel. However, the energy present in these regions is insufficient for Na+ ions to release their water molecules and traverse the channel.
Ion channel gating
Another vital aspect of ion channels involves the dynamic state of their pores. They possess the ability to modify their protein structure, either opening or closing the ion passage. The transformation from one structural state to another is termed gating.
There are three fundamental models which characterize the structural changes ion channels undergo following gating. It is important to note that some ion channels may employ a combination of these models to establish their distinct stable protein configurations:
- In the first model, the structural transformation occurs within a specific region of the channel's lumen. During gating, only the structure within this specific territory undergoes changes to open or close the lumen.
- In the second model, the transition from one functional structure to another involves changes across the entire lumen rather than in a specific region.
- The third model involves a distinct mechanism where no changes take place within the lumen itself. Instead, a particle binds to the lumen's orifice, effectively sealing the ion channel pore.
The structural changes ion channels undergo are linked to specific functional states that can be categorized as follows:
- Activated: In this state, ions can pass through the channel.
- Deactivated: In the deactivated state, no ions pass through the channel. However, with the introduction of specific stimuli, it can be prompted to open and become activated.
- Permanently deactivated or inactivated: When ion channels are in the inactivated state, they do not permit ion passage, but they can also not be activated, even when exposed to appropriate stimuli.
Types of ion channels
The functional states of ion channels are regulated by various stimuli. These can trigger the structural protein changes in each ion channel, providing the energy required to facilitate the structural transition of the channel itself. Ion channels can be categorized into various types based on their activation/deactivation pattern and the specific stimuli they respond to.
Ligand-gated ion channels
These channels are activated or deactivated by a chemical substance binding to a receptor on the channel. This binding induces the opening or closing of the channel's lumen, thereby altering the permeability of ions. Neurotransmitters released in the synapses from the presynaptic membrane are chemical substances serving as stimuli. Ligand-gated ion channels on the postsynaptic membrane, known as ionotropic receptors, undergo a change in structural configuration upon neurotransmitter binding. This enables the activation or deactivation of ion passage through the channel.
Voltage-gated ion channels
These channels are stimulated by changes in the voltage difference across the cell membrane. This voltage change supplies the channels with the necessary energy to promptly alter their structure, either opening or closing the pore. In many voltage-gated channels, fluctuations in the potential difference can result in both the lumen opening for a few milliseconds and the subsequent closure and inactivation of the channel for a few more milliseconds. Once inactivated, the channel becomes unresponsive to voltage changes, even if the potential difference remains or new voltage stimuli are introduced. The cell membrane of the axon hillock and the whole axon are enriched with abundant voltage-gated ion channels that enable the initiation and propagation of action potentials.
Phosphorylation-gated ion channels
In these channels, the stimulus arises from a mechanism that phosphorylates the channel, providing the energy required to open the pore. This phosphorylation can result from the activation of various mechanisms, including those involving G-proteins or other processes triggered by ligands, voltage changes or mechanical stimuli.
Mechanical-gated ion channels
In this type of channels, the stimulus is a mechanical force that either stretches the cell membrane or affects the cell's cytoskeleton. This mechanical force induces a change in the structure of the channel, leading to the opening of its pore. Sensory receptors in the skin, responsible for the sensations of touch and pressure, utilize mechanical-gated ion channels to convert the energy from a mechanical stimulus into membrane depolarization.
Leakage ion channels
In contrast to the majority of ion channels, which typically remain closed and open only in response to specific stimuli, there are channels that remain constantly open for ion passage while maintaining selectivity for different ions. Among these, the Na+ leakage channels and K+ leakage channels are noteworthy, generating a continuous flow of ions, following their electrochemical gradients. Na+ leakage channels permit the passage of Na+ from the extracellular to the intracellular space, inducing partial depolarization of the cell membrane, particularly significant for initiating action potentials in neurons. Conversely, K+ leakage channels facilitate the flow of K+ towards the extracellular matrix leading to hyperpolarization of the membrane.
The activity of ion channels has a profound impact on the functionality of neurons and, ultimately, the neuronal circuits. There are numerous substances that intervene in the operation of ion channels, exerting powerful effects on the entire nervous system.
For instance, benzodiazepines, commonly used medications for treating anxiety disorders, insomnia and certain seizure disorders, act on a type of ligand-gated ion channels known as GABA-A receptors. Gamma-aminobutyric acid (GABA), the primary inhibitory neurotransmitter in the central nervous system, binds to GABA-A receptors, opening the ion channel pore and causing an influx of Cl- into the cell. This leads to hyperpolarization of the postsynaptic membrane and inhibition of the postsynaptic neuron. Benzodiazepines enhance the inhibitory effect of GABA on GABA-A receptors, producing anxiolytic, sedative, hypnotic, muscle relaxant and anticonvulsant effects.
Another example of a substance modulating ion channel activity is phenytoin, an antiepileptic medication, primarily acting on voltage-gated sodium channels in neurons. It selectively binds to the inactive state of these channels, leading to a reduction in sodium influx during the depolarization phase of the action potential. By reducing sodium influx, phenytoin helps avert the excessive and repetitive firing of action potentials. This is particularly relevant in the context of seizure prevention, as seizures involve abnormal synchronized electrical activity in the brain.
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