4. Lectures 9, 10, 11 Flashcards
What are the roles of K+ channels?
K+ channels tend to make the membrane potential more negative and therefore play a role in setting the resting membrane potential, in the repolarization phase of the action potential, in resisting depolarization of the cell towards action potential threshold, and in slowing the rate of firing of action potentials
What are the 4 different types of current in K channels?
- Delayed outward rectifiers
- Transient outward rectifiers
- Ca2+ activated K+ currents
- Inward rectifiers
What are the 5 gene families of K+ channels?
- Kv channels (voltage gated K channels related to shaker family)
- Small conductance KCa channels (Ca activated K channels)
- Large conductance KCa channels (Ca activated K channels)
- Kir channels (inward rectifier K channels)
- K2P channels (2 pore K channels)
Slide 5 lecture 9
What are delay rectifiers (Kvs)?
Delay in activation
Rectifier means current that flows better in one direction than another
Outward rectifier carries current t preferentially outward
Slides 6-7 lecture 9
Why are shaker K+ channels?
The A type channel from drosophila was the first K channel to be cloned
The identification started with a phenotype found in fruit fly
Shaker mutation: these flies shake their legs while under ether anesthesia because they lack a fast transient K current in presynaptic terminals (repolarizing of AP is delayed and release of neurotransmitter becomes enormous causing spasm)
What does “A-type” mean?
Refers to currents that are low threshold, rapidly activating, and inactivating K+ current
Slide 10 lecture 9
How are Kv channels (A-type) inactivated compared to Nav channels?
Slide 11-13 lecture 9
K used ball and chain model and N-terminus mutation
Presence of different β subunits can result in Kv currents with different inactivation properties
Na uses pronase (endopeptidase)
What is the differences in regulating rate at which a cell reaches threshold for AP between the small current A-type outward receiver and the large current A-type outward receiver?
Slide 14 lecture 9
Small current- active at relatively negative values of Vm and tends to hyperpolarize the cell (low level of A type current allows Vm to rise quickly toward threshold which makes short inter spike interval)
Large current- in a spontaneously spiking neuron, a high level of the A type current causes Vm to rise slowly to the threshold (which makes a long inter spike interval)
What is the KCNQ (Kv7) family of K+ channels?
Their genes are mutated in a cardiac condition known as long QT syndrome
Other members of this family are also found in Neurons with their sensitivity to muscarinic INHIBITION and are named M-type currents
Slide 16
How does M current inhibit muscarinic Rs?
A. Stimulation of the preganglionic sympathetic neuron releases acetylcholine which triggers fast then slow EPSP
B. The M current (mediated by a K+ channel) normally hyperolarizes the neuron which inhibits the generation of action potentials (injecting current elicits only a single action potential)
C. Adding muscarine stimulates G protein linked muscarinic receptor and triggers signal transduction cascade that blocks M current which depolarizes with a train of APs
What are the two circumstances BK (Ca activated K channels) channels increase their open probability?
In response to membrane depolarization
Increase open probability as the internal Ca2+ concentration increases
Slides 19-20 lecture 9
What are BK (Ca activated K channels) channels hyperpolarization pauses?
Ca dependant K currents make long hyperpolarization pauses
Accumulation of Ca in a cell during firing of multiple APs can lead to progressively larger Ca activated K current, which can turn off cell during
Slides 21-22 lecture 9
What are the Kir family of K+ channels?
Inwardly rectifying K+ channels have 1 P domain and only 2 membrane spanning segments that correspond to S5-P-S6 (not included in voltage-gated family)
Kir channels pass small outward currents too owing to chronic blockade by intracellular cations
Kir channels contribute to resting potential, they are open at rest
Prevent excessive loss of intracellular K+ during repetitive active and long duration action potentials
Slides 2-3 lecture 10
Slide 6 lecture 10
What are G protein-coupled Kir channels (GIRKs)?
What are they activated by?
Slides 4-5 lecture 10
Have flickering activity
If magnesium is close to membrane, it is depolarized and bonded to pore to block it and make no current
GIRK1 channel is activated by cytoplasmic GTP-γS
What are Katp channels?
Kir - ATP
Inwardly rectifying Katp channels are closed by increases in the ATP/ADP ratio and thereby regulate insulin release in a glucose-dependent manner
In type 2 diabetes sulfonylurea drugs are used to block KATP channels and increase insulin release
Slide 7 lecture 10
What are inwardly rectifying K+ currents?
They are selective for K+ and tend to hyperpolarize a cell and make it less likely to fire an AP
Aren’t gated, but outward flow of K+ is partially blocked by internal Mg2+ at potentials above Ek
There is some outward flow and since cell voltage is never below Ek the function of these channels is to allow flow of K+ ions out of the cell
What are KCNK channels?
Part of K2P family
2P and 4TM topology (slide 11)
Open rectifiers which allow passage of large outward currents
KCNK (pore, leak, or background) channels are not voltage gated, they are open at rest and the main contributors to the resting potential
Slides 11-14 lecture 10
What is open rectification?
KCNK0 currents change in a linear fashion as a function of voltage when the K+ concentration is identical across the membrane
When the concentration of K+ is high intracellularly and low extracellularly a larger outward current is observed
Rectifying because it is not following ohms law
Compare the structures of voltage gated K+ channels, Kir channels, and KCNK channels on slide 15 lecture 10
Okay
What are the 3 reasons channels rectify?
- Unequal ion concentration (open rectification)- current flows more easily from a side of high permeant ion concentration
- Gating- channels can rectify if they only open in a voltage range that favours outward or inward current (some K+ channels show voltage dependant outward rectification because they open with depolarization to voltages where outward K+ flix is favoured
- Block- some channels rectify because they are blocked in a voltage dependant fashion (inward rectifiers of the Kir class allow for the passage of inward current because internal magnesium and polyamines obstruct them when membrane voltage is positive to Ek
How do Ca2+ channels differ from other types of channels?
The influx of Ca2+ causes not only a change in membrane potential, but also acts as a signal to activate processes in the cell
Ca influx activates secretion of neurotransmitters and hormones and thus acts as the trigger for lost kinds of intercellular communication (neurons can’t talk without Ca in cell)
But calcium floating around in cell will kill cell so always need to have enough Ca to put to work
Slide 4-5 lecture 11
How are Ca2+ channels characterized?
Splits into high voltage activated and low voltage activated
High voltage activated- L type Ca channels AND (P/Q, N, and R channels)
L type- large conductance and long lasting current
Low voltage activated- T type Ca channels
T type- tiny conductance and transient current
Slides 6-8 lecture 11
How do you inactivate Ca2+ channels? (Drug)
EGTA drug kills or removed calcium entering channel
The more you increase EGTA, the flatter the curve gets
Slide 9 lecture 11
What is conotoxin?
Group of neurotoxic peptides isolated from the venom of the marine cone snail
5 different types of conotoxin
ω-conotoxin inhibits strongly N-type VGCC (1000 times more effective than morphine)
Since inhibit neurotransmitter release the effect of the conotoxin is analgesic
For L type channels, (P/Q, N, R) type channels and T type channels, what are the characteristics;
Activation range
Inactivation range
ω-CTX GVIA block (conotoxin)
L type Activation: positive to -30mV Inactivation: -60 to -10 mV CTX block: no Dihydripyridine sensitivity: sensitive
P/Q, N, R type Activation: positive to -20mV Inactivation: -120 to -30 mV CTX block: strong for Ca,2.2 Dihydripyridine sensitivity: resistant
T type Activation: positive to -70mV Inactivation: -100 to -60mV CTX block: no Dihydripyridine sensitivity: resistant
Slide 10 lecture 11
What are L type Ca2+ channels function (high voltage activated)?
L type channels underlie most of the HVA current in vertebrae cardiac, skeletal, and smooth muscle
Also in some endocrine
Function: Ca2+ entry in cell that contract or secrete (also source of Ca2+ entry for slow processes such as gene expression)
What do N type channels and P/Q type channels do?
N type- found in neurons, involved in neurotransmitter release, and displayed some properties that were intermediate or neither to L and T types
Fast/efficient release of neurotransmitter release
P/Q- purkinje cells and Q is close to P so PQ
Also responsible for activation of neurotransmitter release
What are T-type Ca2+ channel function (low voltage activation)?
- Selective for Ca2+ (opening cause a depolarization
- Activated at low thresholds and may act to depolarize a cell to reach action potential threshold (most Ca currents are activated at high thresholds)
- Play a role in activating burst firing by generating a slow Ca2+ wave in neuronal somata
Slide 15-16 lecture 11
Study table on Ca channel types slide 17 lecture 11
Ok
Why is Ca2+ so important?
It modulated voltage activation of Na+ channels
Negative shift causes hyperexcitability and spontaneous muscle twitching
Positive shift causes decreased electrical excitability resulting in muscle weakness
It can modulate firing rate by acting on BKCa or SKCa channels (afterhyperpolarization)
Acts as intracellular messenger
