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Questions and Answers
What is the primary characteristic of K+ channels regarding selectivity?
What is the primary characteristic of K+ channels regarding selectivity?
Which of the following receptor superfamilies is characterized by a pentameric structure?
Which of the following receptor superfamilies is characterized by a pentameric structure?
What is the minimum pore diameter of a Na+ channel compared to a ligand-gated receptor channel?
What is the minimum pore diameter of a Na+ channel compared to a ligand-gated receptor channel?
Which type of receptor is not inhibitory in its action?
Which type of receptor is not inhibitory in its action?
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What is the resting membrane potential of neurons typically around?
What is the resting membrane potential of neurons typically around?
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How does selectivity of ligand-gated ion channels compare to that of K+ channels?
How does selectivity of ligand-gated ion channels compare to that of K+ channels?
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Which equation is used to calculate equilibrium potentials for individual ions?
Which equation is used to calculate equilibrium potentials for individual ions?
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What type of signals can neurons integrate?
What type of signals can neurons integrate?
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Which of the following best describes the state of neuronal membrane potential?
Which of the following best describes the state of neuronal membrane potential?
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What is the primary role of ion channels in neurons?
What is the primary role of ion channels in neurons?
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What influences the electrical excitability of neurons?
What influences the electrical excitability of neurons?
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Which part of the neuron is primarily responsible for processing synaptic inputs?
Which part of the neuron is primarily responsible for processing synaptic inputs?
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Which equation accounts for the contributions of multiple ions to the membrane potential?
Which equation accounts for the contributions of multiple ions to the membrane potential?
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What is the intracellular concentration of K+?
What is the intracellular concentration of K+?
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Which ion has the highest extracellular concentration?
Which ion has the highest extracellular concentration?
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What primarily determines the membrane potential in a cell?
What primarily determines the membrane potential in a cell?
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What happens to K+ when it flows down its concentration gradient?
What happens to K+ when it flows down its concentration gradient?
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Why can't Cl- cross an impermeable membrane?
Why can't Cl- cross an impermeable membrane?
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Which ion concentration is least in the intracellular fluid?
Which ion concentration is least in the intracellular fluid?
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What occurs when both K+ and Na+ are completely separated by an impermeable membrane?
What occurs when both K+ and Na+ are completely separated by an impermeable membrane?
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What charge does K+ contribute to the membrane potential?
What charge does K+ contribute to the membrane potential?
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What is the primary intracellular anion mentioned?
What is the primary intracellular anion mentioned?
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What effect does the exit of positive ions (K+) from the cell have on the internal environment of the cell?
What effect does the exit of positive ions (K+) from the cell have on the internal environment of the cell?
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How does the thinness of the membrane influence the membrane potential?
How does the thinness of the membrane influence the membrane potential?
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What is required for a membrane potential to be established?
What is required for a membrane potential to be established?
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What charge is left behind in the cell when K+ ions exit?
What charge is left behind in the cell when K+ ions exit?
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What is indicated by the presence of both positive and negative charges across the membrane?
What is indicated by the presence of both positive and negative charges across the membrane?
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What overall condition is necessary for maintaining membrane potential?
What overall condition is necessary for maintaining membrane potential?
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The cell's interior becomes negatively charged mainly due to which of the following?
The cell's interior becomes negatively charged mainly due to which of the following?
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Why is only a small amount of K+ ions necessary to exit the cell to establish the membrane potential?
Why is only a small amount of K+ ions necessary to exit the cell to establish the membrane potential?
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What does the interaction between positive and negative charges across the membrane help to create?
What does the interaction between positive and negative charges across the membrane help to create?
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Which of the following correctly describes the process affecting membrane potential?
Which of the following correctly describes the process affecting membrane potential?
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What makes Na+ ions unlikely to pass through the sodium channel?
What makes Na+ ions unlikely to pass through the sodium channel?
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Which part of the Na+ channel is crucial for selectivity?
Which part of the Na+ channel is crucial for selectivity?
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What is the primary reason that hydrated K+ is unable to pass through a K+ channel?
What is the primary reason that hydrated K+ is unable to pass through a K+ channel?
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How does the charge of Ca2+ influence its interaction with ion channels?
How does the charge of Ca2+ influence its interaction with ion channels?
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What structural element is different between Na+ and Ca2+ channels?
What structural element is different between Na+ and Ca2+ channels?
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Why is it challenging to select between Ca2+ and Na+ in channels?
Why is it challenging to select between Ca2+ and Na+ in channels?
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Which statement is true regarding the sodium channel's selectivity?
Which statement is true regarding the sodium channel's selectivity?
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What role do the negatively charged groups in the selectivity filter play for Ca2+ channels?
What role do the negatively charged groups in the selectivity filter play for Ca2+ channels?
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What is a consequence of sodium ions being poorly stabilized in their channel?
What is a consequence of sodium ions being poorly stabilized in their channel?
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What amino acids primarily make up the critical DEKA selectivity ring in sodium channels?
What amino acids primarily make up the critical DEKA selectivity ring in sodium channels?
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Study Notes
Membrane Potential & Ion Channels
- Membrane potential is a key aspect of neuronal function
- Ion concentrations (intracellular and extracellular) differ significantly
- Nernst equation calculates the equilibrium potential for a single ion
- Goldman-Huxley-Katz equation calculates membrane potential considering multiple ions
- Ion channel impact on resistance influences the rate of ion flow
- Various ion channel types exist
- Ion channels are regulated by a number of processes
Electrical Excitability
- Neurons are excitable cells driven by electrical signals
- Membrane properties are crucial to neuronal function
- Electrical signalling shows a variety of forms desirable for activity
- Integration of electrical signals is crucial for complex neuronal function, including inhibitory and excitatory signals, spatial and temporal summation. Signalling occurs along dendrites, soma, and axon.
Integration
- Neurons receive inputs from hundreds of thousands of synapses and have inherent activity
- All of this input and intrinsic activity is processed to form the neuronal output
Membrane Potential
- Resting membrane potential is approximately -70mV. This level can vary between cells and also according to the cell condition, and so it is more accurate to describe potential from -50mV to -80mV.
- Neuronal resting potential can vary depending on cell type and cellular condition eg sleep/wake
- Resting membrane potential and most active conductances are mediated by ion channels
Ion Concentrations & Charges
- Extra- and intracellular concentrations of K+, Na+, Ca2+, and Cl- differ significantly.
- Ion movement is influenced by concentration gradients
Permeability
- An impermeable membrane prevents ions from crossing, resulting in no membrane potential
- Permeability allows ions to move and create a membrane potential
Potassium Selectivity
- Leak channels are specific for K+, so only K+ can flow across the membrane
- The concentration gradient of K+ drives the movement out of the cell.
- Membrane potential is primarily determined by K+
Potassium Charge
- Equal positive and negative charges are present on both sides of the membrane
- K+ ions flow down the concentration gradient
- The efflux of K+ ions inside the cell, makes the inside more negative
Few Ions Required
- A small number of K+ ions moving out of the cell are enough to generate a significant membrane potential
- The thin membrane and opposite charges quickly build a potential
- This is sufficient to trigger action potentials, needing a low amount of ion movement
Equilibrium Potential
- K+ ions exit the cell down its concentration gradient and create a negative charge inside the cell
- This negative charge pulls K+ ions back into the cell
- Equilibrium potential is reached when the inward and outward forces are balanced
Nernst Equation
- The Nernst equation calculates equilibrium potential for a single ion
- The equation takes into account the gas constant, temperature, Faraday constant and ion valence and concentration
Nernst Equation (Simplified)
- Simplified Nernst equation for potential calculation for a single valent ion
- Values for room and body temperature are provided
Nernst in Action
- Specific numerical examples of calculating equilibrium potentials for various ions (K+, Na+, Cl-, Ca2+)
Equilibrium Potential
- Equilibrium potential (reversal potential) is used to predict ion flow direction based on membrane potential
- Ions flow down their gradients depending on potential difference
- Chloride movement depends on whether the membrane potential is hyperpolarized or depolarised
Goldman-Huxley-Katz Equation
- Goldman-Huxley-Katz equation is extended Nernst equation to account multiple ions simultaneously.
- The equation includes permeabilities of multiple ions in addition to concentrations
- Example calculation of resting membrane potential is included
Goldman-Huxley-Katz Equation (Calculation Example)
- Numerical example calculation of resting membrane potential using Goldman-Huxley-Katz equation at 37°C
- Example calculation of membrane potential in an A.P.
Membrane Potential (Vm)
- Membrane potential is determined by ion permeabilities and equilibrium potentials of multiple ions. This can range from -70mV to 0mV causing depolarization.
- Ligand gated ion channels can also influence membrane potential
Resting Membrane Potential (Em)
- Resting membrane potential values (approximately -70 mV) are often seen.
- This potential is mostly influenced by K+ and is maintained through passive transport or through ion channels present in the membrane.
- Equilibrium Potential (Ek) greatly influences the membrane resting potential.
Passive Conduction - Dendrites
- Dendrites have a low number of voltage-gated ion channels (Na+ & Ca2+)
- No reinforcement mechanism (all or nothing); unlike axonal signalling
- No myelination; signal weakens with propagation distance
- Current/potential can propagate in either direction by passive conduction
- Signal weakens along dendrite due to leakage ("leaky hose" analogy)
Current Leak
- Current is lost through holes; the larger the diameter, the less resistance or leakage
- Fewer holes in the membrane lead to less leak
Passive Conductance
- Electrical signal spreads along a dendrite but the amplitude becomes smaller as the distance increase. The signal starts with a certain amplitude at the stimulation point, decreasing significantly by the time it propagates to the end of a dendrite.
Dendrites - Soma
- CNS synaptic potentials are usually small and are insufficient to create an action potential for transmission.
- Signals must travel along dendrites to the soma, but decrease in voltage as they transmit.
- To generate an action potential, multiple, coincident (occurring at the same time) and depolarising signals are required.
- Ion channels play a crucial role in modulating signals in dendrites and soma by influencing excitability.
- Neurotransmitter release in synapses is also regulated by ion channels.
Considerations
- Ion channel influence on cell excitability
- Generating electrical circuits. This is influenced by channel activity
- More channels open, lower resistance, greater leak
- A current generates lower electrical potential across a dendrite due to channel resistance and leakage
- Neurotransmitter release and intracellular messenger systems regulate ion channels
Ion Currents
- Ionic currents mostly involve Na+, K+, Ca2+, and Cl-
- Ca2+ currents are too small to majorly influence membrane potential yet are critical for signalling
- Mammals have different types of Na+, Ca2+, and K+ currents
Ion Channels
- Leak channels passively allow ion flow regardless of the membrane potential
- Gated channels open or close in response to stimuli (voltage, ligand, etc.)
- Some channels rectify, preferring certain currents at certain voltages
- Ion channel activity can be modulated by various factors
Leak Channels
- Individual leak channels randomly open and close, unlike constant-open aqueous pores.
- Recording of individual channel activity reveals their fluctuating nature
- Multiple channels contribute to overall current related to membrane potential
Gated Channels
- Voltage gated channels respond to changes in the membrane potential
- Ligand-gated channels open or close in response to binding of specific molecules (ligands)
- Ligands may be extracellular transmitters, intracellular ions or nucleotides
- Other gated channels respond mechanically to changes.
I/V Relationships
- Channels often show direct relationships between current (I) and voltage (V)
- Different ions (Na+, K+) may show different relationships
Rectification
- Channels may rectify, favouring certain current direction/amplitude at given voltages as current may flow more easily in one direction than the other, due to the ion channel itself.
- Na+ and K+ channels may respond differently
How do we selectively record ion currents
- Drugs selectively block ion channels
- These drugs, which are usually ion channel blockers, allow the isolation of individual ion currents. Techniques such as single-channel recordings are also used to study channels at a more detailed level.
Structure & Function of Ion Channels
- Overview of ion channel function, structure, and the factors that determine ion selectivity in a channel. This is crucial for membrane signalling and its function.
Potassium Channels
- Found in most species
- High structural and functional similarity
- Have various types; classified into 4 major groups
- Includes voltage-gated, inwardly rectifying, two-pore domain, and ligand-gated K+ channels.
Basic Structure
- Ion channels have numerous subunits, that vary across different types. Some channels can have other auxiliary subunits.
- Each subunit consists of multiple transmembrane domains & includes a pore domain, formed due to an internal loop, which contains the selectivity filter amino acid sequence.
Pore
- Pore structure highly conserved within different types of channels
- Pore's selectivity filter formed by an intramembrane loop, located between two transmembrane domains
- This filter contains specific amino acid sequences regulating selectivity.
K+ channel Gating
- Gating is the opening/closing of the channel.
- Channels generally have three states: resting (usually closed), activated (open), and inactivated (closed)
- Channels have gates, located intra- and extracellularly.
Gates
- Extracellular gate usually formed by the selectivity filter
- Intracellular gate may form by voltage sensors.
- Inactivation (closed -> open -> inactivated -> closed) can occur and may happen by different mechanisms depending on the channel.
VGKC - Kv
- Channels with 6 transmembrane segments, including a pore loop for selectivity
- Channels have a voltage sensor
- Essential for cell repolarisation
- Opening with cell depolarisation, closing during hyperpolarisation
Kv (Potassium Channel)
- Structural details like transmembrane (TM) domains, the voltage sensor, and the location of the pore and associated subunits
Other Potassium Channels
- Potassium channels show diversity in types, especially the two-pore domain or inwardly rectifying channels and ligand gated K+ channels.
- Types like K2P or Kir have structures distinct from voltage-gated channels.
- Specific roles in hyperpolarisation or upon specific ligand binding
Sodium Channels (Nav)
- Sodium channels are voltage-gated, highly similar to voltage-gated potassium channels. They consist of a huge monomeric protein with 4 6TM segment domains.
- The pore is formed by loops in the segments 5 and 6. A voltage sensor occurs in segments 1 to 4.
- Additional regulatory β proteins exist.
- Inactivation occurs in the loop between domains 3 and 4.
- Sodium leak currents may also occur through sodium channels.
Sodium Channels (NaV)
- Structural details like transmembrane (TM) domains, the voltage sensor, regulatory beta subunit, and the inactivation gate.
Ca2+ Channels
- Ca2+ channels can be either voltage-gated or ligand-gated.
- Includes various types like L-, P/Q-, N-, R-, and T-type, each with specific properties.
- Many ligand-gated or other types are present. Some are slightly permeable to sodium.
Cav Channels
- Heteromeric channel with α1, α2δ, β, and γ subunits crucial for function.
- α1-pore subunit similar to that of Na+ channels
Cl- Channels
- Chloride channels are poorly understood and may have varying properties.
- CFTR is a notable example. A wide variety of types are known.
Ion Channel Selectivity
- Ion size and charge influence ion channel selectivity
- Negative charges repel negatively charged ions; positive ions are attracted.
- Mechanisms for selecting among different positive ion sizes will be examined in detail.
Potassium (K+) Channel Selectivity Filter
- TVGYG selectivity filter in all K+ channel subunits
- 4 binding sites (S1-S4) on carbonyl groups
Energetics
- Ions treated as point charges
- Interactions with negative charges are favoured energetically due to ion stabilisation
- Ions have solvation shells in the solution, and can form bonds or interactions with water molecules
Movement of K+ Ions
- K+ is strongly positive; attracts water molecules from solution
- Amino acids have carbonyl groups that have specific distances relative to K+ as in water
- Carbonyl groups enhance K+ stability by replacing the water molecules
- K+ ions pass through the channel by alternating with water molecules
Selectivity K+ > Na+
- Na+ atoms also attract water molecules (hydration)
- Na+ ions too small to interact with all carbonyl groups
- Energetically unfavourable to remove water molecules around Na+ ions. This prevents Na+ ions from passing through the channel
Na+ Channel Selectivity Filter
- Sodium channels have two selectivity rings, termed outer and inner.
- The inner ring comprises DEKA as its amino acid residues, while outer rings have less impact in determining ion selectivity
- Amino acid side chains present in outer rings do not usually influence ion binding or movement.
Selectivity Na+ > K+
- K+ ion size with its hydration shell is too large to pass through the channel
- Energetically unfavourable to remove water around the K+ compared to Na+
- This difference influences ion conduction through the channels
Ca2+ Channels
- Ca2+ size similar to that of Na+, making selection complex
- Ca2+ bears a double positive charge
- Increase in negative charges in the selectivity filter is required
Selectivity Na+/Ca2+ Channels
- Stabilization of positive ions is crucial for energy favouring. Na+ is not stabilised, while Ca2+ is well stabilised
Ca2+ Channel Selectivity Filter
- Na+ channels have DEKA selectivity ring
- Ca2+ channels have 4 COO - groups
- Ca2+ channels are favoured by a smaller pore diameter
Fun With Molecular Biology
- Modifying ion channels for different purposes is feasible
- No ion channel is entirely ion-specific
- Selectivity varies substantially across different ion channels
- Concentration gradients also influence ion flux significantly.
Receptor Ion Channels
- Overview of receptor channels and their key properties; also related to the different superfamilies.
- Properties like ion selectivity and pore size are key
Main Ionotropic Receptors
- Key ionotropic receptors in CNS, including their main neurotransmitters and roles
Receptor Superfamilies
- Different types of receptor superfamilies; examples include Cys-loop or Glutamatergic receptors based on their structures and the ligands they bind, and related receptor mechanisms
Receptor Channel Opening (Basic Concept)
- Receptor subunits arrange; hydrophobic side chains prevent ion entry in a closed configuration
- Binding of a specific ligand changes the protein conformation, allowing ions to pass
Receptor Pores
- Receptor pores are generally larger compared to other ion channels
- Minimum pore size varies, lower than that of a potassium channel
- Ion selectivity in receptor pores is lower because of the physical size of the pores.
- Exception to this is AMPA or Kainate receptors which do not conduct calcium.
CNS Ionotropic Receptors
- Fast control of excitability via ion flux
- Excitatory receptors (AMPA, Rs, NMDAR) for the brain
- Inhibitory receptors like GABAAR and glycine receptors
- Other types such as 5-HT3, nAChR have more fast modulatory roles, as it is less likely for them to trigger an AP
Summary
- Ion channel selectivity: K+, Na+, and Ca2+ selectivity varies substantially among channels
- Wide differences in ion pore structures and properties; particularly in voltage-gated channels
- Selectivity filters and energetics of ion hydration determine ion permeability
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Description
Test your knowledge on the pivotal role of ion channels in neuronal function, including selectivity and membrane potential. This quiz covers essential concepts related to K+ channels, Na+ channels, and ligand-gated receptors. Strengthen your understanding of how neurons communicate and process synaptic inputs.
