Ion Channels: Module 1.9 - 1.13 Flashcards
What are the Ion channels grouped into?
Superfamilies
Superfamilies thought to evolved from common ancestral gene by gene duplication and divergence.
The transition of a ____ between different conformational states is called ____.
The transition of a channel between different conformation states is called gating.
What are the different subunit arragments to form an ion channel?
What are the 3 different physical models for the opening and closing of Ion channels?
- Localized conformational change
- Generalizer structural change
- Blocking particle
What are 3 major transduction mechanism that control channel opening in neurons?
- Ligand Binding (Extracellular, Intracellular, Phosphorylation)
- Voltage Changes
- Mechanical Force(Stretch activated)
How are Inactivation of voltage gated Na and K channels thought to occur?
Through a conformational change.
How are voltage gated Ca channels thought to inactivate.
Requires influx of Ca to bind to Calmodulin which then binds to the Ion Channel to inactivate.
How many domains does a Alpha sub-unit of a voltage fated K+ channel have?
6
S1 - S6
What is the pore forming region of the Alpha subunit of a voltage gated K+ channel?
P Domain
Lower Hydropathy Index - Less Hydrophobic
What segment acts as the voltage sensor in the Alpha Subunit of voltage gated K+ channel?
S4 Segment
Has large number of positively charged lysine and arginine residues.
How many Alpha subunits are required to make a completed Voltage gated K+ ion channel.
4
Always need 4 P regions
Can have accessory subunits(Beta etc)
How many Alpha sub units are required to form a complete Na or Ca Channel?
1
Single polypeptide with 4 homologous repeats.
Why does Na+ behave as if it is larger than K+?
Has more layers of hydration.
Do smaller or larger ions attract more water?
Smaller
More localized charge and stronger electric field.
Who was the first to propose that channels have selectivity filters?
Bertil Hille (1970 - 1973)
What is the selectivity filter?
Narrow region of channel where ions must shed layers of hydration if its energetically favorable to form electrostatic bonds with selectivity filter in order to traverse the channel.
Describe the process of the K+ selectivity filter.
K+ ions enter the Inner Chamber from the Cytoplasmic side. The ion that was previously in the inner chamber jumps to site 4 moving ions in the outer configuration (site 1 and 3) expelling 1 ion. Now there is 2 ions at site 2 and 4(inner configuration)which jump to the outer configuration.
Describe the process of the Na+ Selectivity filter.
Glutamate and Aspartate Residues(with - charged carboxylic acid groups) attract cations and repel anions at the mouth of the pore. Pore is lined with oxygen and Carboxylic Acid allow Na to temporarily shed layers of hydration and form interactions with them.
Na Channels can allow sever water molecules
Why dont K ions cross through the selectivity filter of a Na channel?
Size of Partially hydrated K ion is too large for Na selectivity filter.
Why dont Na+ ions cross the selectivity filter for K.
Electrostatic interactions between Na and K selectivity filter are energetically unfavorable.
Needs to be more favorable than losing hydration layers.
What is the distinctive pattern found in the S4 domain?
Every third position contains an arginine or lysine residue.
Present in all voltage gated channels - and absent in voltage gated
What links the Voltage sensing domain(S1-S4) with the pore domain(S5-P-S6)?
Short Coupling Helix (S4-S5)
How does a voltage gated K channel close?
Membrane repolarization causes the downward movement of the S4-S5 helix, applying force to the S6 inner helix causes it to bend and close the gate of the channel.
What type of chart can tell you evolutionary relationship between channels?
Dendogram
What type of channels are Nav closely related to?
Cav
How many members are there in the Nav channel family?
9(Nav 1.1 - 1.9)
There is a Nax channel however it is not voltage sensitive
Each neuron has all of these, but variable composition differentiates neurons.
What channel is the Nax channel most closely related to?
Nav 1.7
Nav channels can be classified by there sensitivities to TTX
Describe the 2 classes and which Nav channels fall under those classes?
TTX Sensitive - Nav 1.1, 1.2, 1.3, 1.4, 1.5, 1.7 - Can be blocked by micromolar concentration of TTX
TTX Resistant - Nav 1.5, 1.8, 1.9 - Can be blocked with Micromolar concentrations of TTX
What are the Nav channels that contribute to the AP and what are their role?
Nav 1.3 expressed greater in hypersensitive areas.
What current precedes current generated from the influx of sodium?
Gating current - Brief ouward movement of positive charges within the Nav channels.
How does Nav channel gating work?
Initial depol causes S4 unites to repel upwards activating the channel. When there is enough depol, all S4 sub units will push upwards initiating the inactivation gate.
What is pronase?
Pronase is a mixture of several nonspecific endo and exoproteases that digest proteins down to single amino acids. Pronase digests the Nav inactivation gate.
How does extracellular calcium concentration affect the open probability of Nav channels?
More extracellular calcium will repel S4 movement upwards that cause activation of the channel. You need more depolarization to push S4 up in the presence of more Calcium.
What is inherited erythromelalgia and what is it caused by?
Complex pain and erythema of the hands and feet. The disorder usually starts in the feet but can affect the hands and, occasionally, the nose and ears. Pain is relieved by cooling.
**Caused by a Gain of Function Mutation in Nav 1.7. Shift in Activation voltage of it. **
What are the 3 families of Cav channels?
L-Type
T-Type
(N, P/Q, R) - Type
What familes of Cav are HVA and LVA and what do their respective currents look like?
L-Type (HVA): Large conductance and long lasting current.
T-Type (LVA): Tindy conductance and transient curent.
What speed of inactivation do T-Type Ca channels have?
Fast Inactivation
How are Cav channels inactivated and what molecule can reduce inactivation?
Free [Ca] in cells can bind to channel and inactivate it.
EGTA : Calcium Chelator - Makes [Ca] drop inside cells.
What are the blockers of the various Cav channels?
Explain T-Type Ca Channels role in Burst Firing.
What are some Cav related Channelopathies?
The K channel superfamily is large and diverse;
What are the different types of currents of K channels?
- Delayed Outward Rectifiers (Kv Family)
- Transient Outward Rectifiers (Kv Family)
- Ca activated K currents
- Inward Rectifiers
- Background K channels
Explain the delayed rectification in Kv Channels.
“Delayed” - refers to the delay in activation compared to the ativation of Na channels.
**“Recifier” **- rfers to a current that flows better in one diretion than another. Outward Rectifier - preferentially caries current out.
What is the trick to finding Ek in the I-V plot of a KV channel?
Use symmetrical K solution.
What is the structure of the Alpha subunit of the Kv Delayed Rectifier group?
The alpha subunit of a voltage-gated K+ channel
(Kv) subunits have a 6TM, 1P region, and a S4
that acts as a voltage sensor. Kv channels are
activated by depolarization. The current trace
is based on KCNQ1, a delay rectifier.
What are the different types of inactivation of Kv(A-Type) channels?
Explain how the inhibition of M current by muscarinic receptors work.
What do BKCa channels increase their open probability to?
Membrane Depolarization: High Potentials - +40mV.
Intracellular [Ca}
Explain what phase of AP does BKCas help with and how it can shut off burst firing.
**Afterhyperpolarization Phase **
Long Quiet Periods in Burst Activity
