Selectivity / Permeability / Conductance Flashcards
What are the general principle of Ion Selectivity?
- The concentration of the selected ion in the channel should be similar to that in the external and internal solutions.
- The dielectric constant (also known as relative permittivity) is a measure of how well a material can insulate against the transmission of an electric field. In simpler terms, it reflects a material’s ability to permit or resist the transmission of electrical forces.
Describe the ion selectivity of K channels
- In K channels, the selectivity filter is lined with carbonyl oxygens that tightly bind dehydrated K+ ions, similar to their binding with water molecules in solution.
- The filter has a lower dielectric constant compared to water.
A lower dielectric constant implies that the material (in this case, the selectivity filter) is less effective at permitting the transmission of electrical forces. Because of this lower dielectric constant, the binding of carbonyl oxygens to potassium ions needs to be tighter than the binding of water oxygens. Tighter binding compensates for the reduced ability of the filter to permit the transmission of electrical forces, ensuring effective ion selectivity. - Carbonyl groups provide extra binding energy due to their higher dielectric constant (2.3 D or more) compared to water (1.83 D). The higher dielectric constant of carbonyl groups enhances their ability to bind with potassium ions, contributing to the efficiency of the selectivity filter in K channels.
Describe the ion selectivity in Na channels
- Na/K selectivity in sodium channels is 10/1 or less, depending on the measurement method.
- Channel filter region: Cross-section of about 3 × 5 A, large enough for Na+ ion with one water molecule.
- Filter has a negative charge, aiding in the required binding energy for selective Na+ passage.
What is the signature sequence in the selectivity filter of K-channels?
Signature sequence is (T1X2X3T4X5G6Y7G8, TXXTXGYG) identified, with the GYG motif being highly conserved.
Why are voltage gated K channels different from Navs and Cavs in regards to selectivity filter?
Voltage-gated K channels are opposite the monomeric Navs and Cavs, either tetrameric or dimeric.
- The structure of KcsA reveals a tetramer with fourfold symmetry and a clear pore along the fourfold symmetry axis.
- Each subunit contains two transmembrane domains (T1 and T2).
- Between the T1 and T2 helices a short helix (the pore helix) is positioned such that its C-terminus points into the center of the channel pore.
- Immediately following this helix, the selectivity filter loop containing the signature sequence residues, T72A73T74T75V76G77Y78G79, extends into the center of the channel. The backbone carbonyl oxygens of Y78, G77, V76, and T75 as well as the side-chain hydroxyl of T75 point directly into the center of the protein, forming the narrowest region of the channel pathway. These oxygens coordinate dehydrated K+ ions as they permeate the pore, surrounding each K+ by eight oxygen atoms in a cage-like structure.
- The four potassium binding sites are numbered S1–S4, starting from the most extracellular cage formed by the backbone carbonyls of Y78 and G77 (the S1 site), and ending with the most intracellular cage formed by the side-chain hydroxyl and backbone carbonyl oxygens of T75 (the S4 site).
What are the structural basis for the selectivity in Na channels including the signature sequence in the selectivity filter?
- The Na+ channel features a rectangular opening (approximately 3 × 5 Å) surrounded by oxygen atoms and a negatively charged carboxylate ion.
- Na+ ions conduct through the channel in a partially hydrated state.
Selectivity Factors:
* Na+ selectivity follows the electrostatic model of Eisenman (1962).
- Cloning and sequencing of mammalian voltage-gated Na channels revealed the presence of the DEKA motif.
- Mutations within the DEKA motif, particularly the substitution of glutamate, have significant effects on selectivity.
Filter Structure and Function:
* Bacterial Na channels with glutamates create a constricted region within the channel, allowing for the partial hydration of conducting Na+.
* Solvent molecules play a role in rehydrating Na+ as it traverses the filter.
* Molecular dynamics simulations illustrate that Na+ can occupy two sites simultaneously, which are weakly coupled.
What is the signature sequence in the selectivity filter of Ca-channels?
EEEE, glutamate x 4
Definition of ion conductance
Ion conductance is a measure of the ease with which ions flux across the membrane.
Ion conductance can be calculated:
From measurements of electrical current generated by the movement of ions through the membrane, normalized to the voltage applied across it (via voltage-clamp) by simply using Ohm’s law (g = I/V).
Conductance is the inverse of resistance (g = 1/R).
g is given as S, Siemens and R is given as Ohm
What affects the conductance?
Ion selectivity does not vary widely within a channel subfamily, conductance levels can vary dramatically.
Channel conductance is dependent on many factors, such as:
- pore chemistry
- pore length
- the size of the cavity
- rates of dehydration
- electrostatics
- the energy landscape
- rigidity of the selectivity filter
- pore occupancy
- ionic conditions
What is the difference between selectivity, permeability and conductance?
Ion Channel Selectivity:
* Refers to the preference of ion channels for specific ions based on their size and charge.
* Ion channels may be selective for cations (e.g., Na+, K+, Ca2+) or anions (e.g., Cl-).
* Selectivity is determined by the structure of the channel’s pore and the presence of specific amino acid residues.
Ion Channel Permeability:
* Permeability describes the ease with which ions can pass through an ion channel.
* It depends on factors such as ion channel structure, selectivity, and gating properties.
* Permeability is a key factor in determining the flow of ions across cell membranes.
Ion Channel Conductance:
* Conductance is a measure of the ease with which ions can move through an open ion channel.
* It is influenced by factors like ion channel diameter, charge, and the presence of specific residues.
* Conductance is a crucial parameter in understanding the electrical properties of ion channels and their impact on cell function.
Summarize the selectivity, permeability and conductance abilities for Kvs
Selectivity:
The selectivity of voltage-dependent K+ channels is primarily attributed to specific amino acid residues in the channel’s pore region, forming a selectivity filter.
* Amino Acid Residues: The selectivity filter typically contains conserved amino acid residues, including threonine (Thr) and valine (Val).
* Example: In the Shaker-type K+ channels, a signature sequence called the TVGYG motif contributes to K+ selectivity. The oxygen atoms from the backbone carbonyl groups of threonine interact specifically with K+ ions, allowing their passage.
Permeability and Conductance:
The diameter of the pore and the presence of these specific amino acid residues contribute to the permeability and conductance.
* Example: The open conformation of the K+ channel pore allows the passage of hydrated K+ ions, while excluding larger ions like Na+. The conductance is high when the channel is open, facilitating the efficient movement of K+ ions.
Summarize the selectivity, permeability and conductance abilities for Navs
Selectivity:
Voltage-dependent Na+ channels are selective for sodium ions due to the arrangement of amino acid residues in the selectivity filter.
* Amino Acid Residues: The selectivity filter in Na+ channels often includes aspartic acid (Asp) and glutamic acid (Glu) residues.
* Example: In the DEKA motif of the selectivity filter in sodium channels, the negative charges from aspartic acid and glutamic acid residues interact favorably with sodium ions.
Permeability and Conductance:
The structure of the channel pore and the specific arrangement of amino acids determine the permeability and conductance.
* Example: When the voltage-dependent sodium channel is open, it allows the rapid influx of sodium ions, leading to a high conductance state.
Summarize the selectivity, permeability and conductance abilities for ASICs
Selectivity:
ASICs are permeable to cations, and their selectivity is influenced by amino acid residues in the channel pore.
* Amino Acid Residues: ASICs contain acidic residues such as glutamate and aspartate that contribute to cation selectivity.
* Example: In ASIC1a, a subunit of ASICs, glutamate residues in the channel pore contribute to the selectivity for sodium ions.
Permeability and Conductance:
The conductance of ASICs is influenced by the interactions of ions with specific amino acid residues in the channel.
* Example: When the channel is activated by a decrease in pH, it allows the influx of cations, particularly sodium ions, leading to changes in membrane potential.
Summarize the selectivity, permeability and conductance abilities for ligand-gated ion channels (NMDA etc.)
Selectivity:
Ligand-gated channels, like NMDA receptors, exhibit selectivity based on the structure of their pore and specific amino acid residues.
* Amino Acid Residues: NMDA receptors have residues such as arginine that contribute to ion selectivity.
* Example: The pore region of NMDA receptors is selective for calcium ions in addition to monovalent cations like sodium.
Permeability and Conductance:
The conductance of ligand-gated channels is influenced by the binding of ligands and conformational changes.
* Example: When glutamate binds to the NMDA receptor and the membrane is depolarized, the channel undergoes conformational changes, allowing the influx of calcium ions and contributing to synaptic plasticity.
What is the signature sequence in the selectivity filter of NALCN?
NALCN selectivity filter:
NALCN contains the amino acids: EEKE
OBS opposite of other Na-channels which all have DEKA.
