Brainscape's Knowledge GenomeTM

Browse over 1 million classes created by top students, professors, publishers, and experts.


See full index

Jacopo Biomembranes > Lecture 18 > Flashcards

Lecture 18 Flashcards

1
Q

How many K+ channels have been found in the human genome?

A

There are over 70 K+ channels gene in the human genome (K+ channels are the most diverse group of ion channels), and many of these have been cloned and examined in detail.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
2
Q

What are three physiological processes that involve K+ channels?

A

Control of cell Volume
Control of membrane potential and cell exctitability
Secretion of salts, hormones and NTs.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
3
Q

List some of the intrinsic and extrinsic factors that regulate K+ channels activity:

A

1) numerous hormones and transmitters
2) Voltage across membrane
3) Concentration of Ca2+ or ATP in cytoplasm
4) Kinases and phosphatases
5) G-proteins

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
4
Q

What are the three classes of potassium channels based on their structure?

A

1) Six transmembrane one-pore
2) Two-transmembrane one-pore
3) Four transmembrane two-pore

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
5
Q

Describe 6-transmembrane segment K+ channels:

A

The α subunit of these K+ channels resembles a single domain for Na+ or Ca2+ channels.
Contains S4 voltage sensor and P region
G(Y/F)G in P loop confers selectivity.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
6
Q

What is the functional and structural role of α subunit in 6-transmembrane segment K+ channels?

A

Each α subunit contributes a quarter of total tetrameric channel.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
7
Q

What are four memebrs of the 6-TM K+ channels class?

A

Voltage-activated K+ (K+V) channels
hERG channels
Ca2+ -activated K+ channels
KCNQ channels

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
8
Q

What are voltage-gated K+ channels responsible for?

A

The shaping of action potential

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
9
Q

What are the two maint types of K+v in native cells?

A

1) Inactivating (A) type

2) Non-inactivating (delayed rectifier)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
10
Q

Describe A type Kv channels:

A

They display rapid inactivation following opening-currents which displayed no inactivation.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
11
Q

What did deletion of residues 6 to 46 cause in Kv type A?

A

It caused currents which displayed no inactivation.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
12
Q

What causes inactivation in Kv type A?

A

Inactivation is caused by first 20 amino acids which forms compact hydrophobic/charged surface domain (the ball).

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
13
Q

What causes the “chain” structure in Kv type A?

A

The 50-60 amino acids following the first 20 (the ball).

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
14
Q

What determines the ion selectivity in Kv?

A

Ion selectivity for Kv is determined by carbonyl backbone groups of the TVGYG motif in the P loop.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
15
Q

Describe the “ball and chain” model of Kv channel inactivation:

A

This blocking particle inactivation mechanism is also referred to as N-type inactivation (because it involves N-terminal structure). A set of amino acids in the S4-S5 loop (near the internal channel mouth) are thought to constitute the receptor for the inactiviation ball.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
16
Q

Do all the cloned α subunit display inactivation of K+ currents? Explain why:

A

No, not all cloned α subunits display inactivation. Addition of β subunit can induce fast inactiation in some.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
17
Q

Describe Ca2+-activated K+ channels:

A

K+ channels whose activities are controlled by the concentration of cytoplasmic calcium. They play a role important roles in limiting Ca2+ entry and neuronal excitablity.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
18
Q

What are the three main subtypes of Ca2+-activated K+ channels based on their single channels conductances?

A

1) Large conductance (roughly250pS) K+ channels: also known as BK, Kca or Maxi-K channels
2) Intermediate (IK) conductance (60-100pS) channels
3) Small (SK) conductance (<20pS) channels.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
19
Q

What are SK responsible for in neurons?

A

They are responsible for the more persistent slow afterhyperpolarisation (AHP) observed after action potential dischargers.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
20
Q

Where are Maxi-K expressed and what is their function?

A

They are expressed ubiquitously (except heart): in neuronsthey help shape action potentials and regulate transmitter release whereas in smooth muscle they help regulate contractile activity and tone.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
21
Q

Describe Maxi-K channels:

A

They are voltage-dependent and so opening is controlled by transmembrane voltage (gated by depolarisation).

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
22
Q

Define the peculiarity of the activation voltage of Maxi-K channels:

A

The activation voltage is not fixed, but is dependent on the intracellular Ca2+ concentration (increasing Ca2+ allows channel to open at physiological voltages).

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
23
Q

What is the correlation between Ca2+ intracellular concentration and the activation voltage for Maxi-K channels?

A

As the Ca2+ concentration in the cell increases the channel requires less electrical energy to open.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
24
Q

Describe the Maxi-K channels structure:

A

Extra transmembrane domain at N-terminal region result in exoplasmic NH2 terminus (i.e- 7 TM structure). Long COOH terminus ‘tail’ region that is important for function.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
25
Q

What gene encode for Maxi-K α subunits?

A

A single gene (Slo) encodes Maxi-K α subunit. Diversity is provided partly by multiple alternative splice exons in the Maxi-K gene. 3 other members of the Slo family are found in mammals (different properties).

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
26
Q

Describe the primary sequence of Maxi-K channels:

A

The primary sequence is homologous to Kv channels, although SO is unique to Maxi-K channels (Slo 1 and 3, but not 2.1 and 2.2).

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
27
Q

What is the role of accessory β (β1-β4) in Maxi-K channels?

A

They interact with Maxi-K α subunit. This alter sensitivity to Ca2+ and voltage, activation kinetics and pharmacology.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
28
Q

Why is the S0/N-terminal domain important in Maxi-K channels?

A

It is required for β subunit modulation of the channel.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
29
Q

Describe the α subunit primary sequence in Maxi-K channels:

A

It contains possible phosphorylation sites and additions of slice insertions adds more resulting in channels differentially regulated by protein kinases/phosphatases (PKA, PKC and PKG).

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
30
Q

Describe Maxi-K 2 independent sensing mechanisms:

A

Maxi-K has both voltage-gating and ligand-gating domains with low probability of the channel being open when neither calcium nor voltage are activated.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
31
Q

What is the topology of Maxi-K channels?

A

Typical general topology of the Kv channels with S4 region acting as the voltage sensor.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
32
Q

What does ligand-gating mechanism of Maxi-K generally requires?

A

Ligand gating mechanism involves specialized structures oresent in the C-terminal region of the protein.

33
Q

What is found at the C-terminal of Maxi-K channels?

A

Additional hydrophobic segments (S7-S10) are present at the C-terminus, with a linke region between S8 and S9 denoting the tail domain.

34
Q

Describe Site 1 of Maxi K

A

It is called RKC (regulators of conductance of K), it contains S7 and S8. RKC domains contribute to the biding of intracellular ligand. Calcium RKC domains are proposed to form intracellular gating ring.

35
Q

What does binding of Ca2+ to RKC results in?

A

Binding of Ca2+ expands ring, which acts on S6 gates and open channels.

36
Q

What does the tail domain of α subunit determines?

A

It also determines Ca2+ sensitivity to channel- region between S9 and S10- contains a series of negatively charged (D) residues. This region is known as the calcium bow and mutations here affect high affinity sensing of calcium. Calcium bowl is though to interact with the RKC domain to confer calcium sensing to maxi-K channels.

37
Q

What effect does increasing intracellular calcium binding to RKC and calcium bowl (on Maxi-K channels) have?

A

It increases the opening force of the channel gates and leads to increased channel openings. The voltage sensor, independently, adds to this force on the gates (via S4 drive conformational change) and increases channel open probability.

38
Q

Why is sensitivity to calcium so important in the physiological roles of Maxi-K?

A

It makes Maxi-K channels an important negative feedback system for calcium entry in many cell types.

39
Q

List the physiological roles in nervous system of Maxi-K channels:

A

Plays an important role in timing of bursts of action potentials- contribute to afterhyperpolarization (AHP) and is part of refractory period for firing.

40
Q

List the physiological roles in vascular reactivity of Maxi-K channels:

A

An important role in vascular reactivity (as they induce hyperpolarization and balance the effects of excessive vasoconstriction), it opens in response to local elevations of Ca2+ (calcium release via ryanodine receptor) and relax smooth muscle (close calcium channels)

41
Q

What does loss of β subunits of Maxi-K channels correlate with?

A

It correlates with hypertension (no β1 subunit- maxi-K is less Ca2+ sensitive and so get increased arterial tone and BP).

42
Q

Why are Maxi-K channels important for audition?

A

Maxi-K channels provide a mechanism for cochlear hair frequency tuning (basilar membrane): various splice variants of α subunit, in combination with β subunits and Ca2+v channels determine frequency to which each hair cell responds (frequency encoding in hearing).

43
Q

Desribe the Maxi-K channels and Vascular Smooth Muscle (SVM) relaxation process:

A

Ca2+ release by CICR via ryanodine receptors causes local increase in [Ca2+]i that activates BK channels and gives K efflux. Membrane hyperpolarizes closing Ca2+V that gave initial depolarization and contraction.
Vascular smooth muscle.

44
Q

Where are Maxi-K channels present at high levels?

A

They are present at high levels in axon terminals, somas and dendrites.

45
Q

What is the influence that Maxi-K channels have on RMP?

A

Generally they have little difference on RMP but when activated by increased intracellular Ca2+, Maxi-K depresses excitability.

46
Q

What effect does AP entering the axon terminal has on MAXI-K channels?

A

Following AP invasion of terminal, Ca2+ entry through Cav acts to open Maxi-K and this limit release.

47
Q

What effect do Maxi-K blocking agents have?

A

They enhance transmitter release.

48
Q

What do Maxi-K “openers” do?

A

They reduce transmitter release presently lack selectivity to be of clinical use.

49
Q

What does Maxi-K contribute to at the level of the AP_

A

Both to repolarization and the AHP.

50
Q

What effects does blocking Maxi-K have on the AP?

A

Broadens action potential.

Diminishes the AHP.

51
Q

Describe the 2/TM domains K+ channels:

A

One pore family consist of the inward rectifier (KIR). These channels conduct K+ currents more in the inward direction than the outward direction and help set resting membrane potential.

52
Q

Describe 4-TM domains K+ channels:

A

Two (tandem) pore family are weak inward rectifiers. Most abundant class of K+ channels. Act as a background channels and help set the resting mebrane potential.

53
Q

Describe TREK1:

A

Neuronal background channels. They contain 2 P loops, therefore, it only requires 2 subunits to form a functional channel. TREK1 channels are signal integrators and respond to many inputs.

54
Q

Describe K2P channels:

A

They are constitutively open at rest and contribute to RMP- TREK 1 channel activity is controlled by numerous factors.

55
Q

Describe the ideal background current.

A

Follows the GHK equation, is voltage independent.

Its amplitude immediately follows membrante potential and it is not rectifying.

56
Q

List the inputs to which TREK1 respond:

A 
Mechanical deformation
Internal pH reduction
heat (32-37 degrees)
Intracellular lipids (e.g PIP2)
Fatty acids (eg. arachidonic acid)
All of these increase channel opening and cause hyperpolarization of RMP.
57
Q

How does inhibition of TREK1 channel opening occurs?

A

Through phosphorylation at intracellular sites via PKC and PKA. Also various volatile (eg. halothane, diethyl ether) and gaseous (nitric oxide, cyclopropane) anaesthetics agents open TREK1.

58
Q

What do TREK1 KO mice tell us about its function?

A

1) Decreased sensitivity to anaesthetics- channel contributes to cellular mechanism of general anaesthesia
2) Mice are more sensitive to brain ischemia and epilepsy- loss of neuroprotection from polyunsaturated fatty acids.
3) Mice are more sensitive to painful heat and mechanical stimulation - hyperalgesic, especially to inflammatory pain.
4) Less inclined to give up when placed in a stressfull environment - mood regulation, they are in an antidepressant state.

59
Q

What happens when TREK1 opens in the presynaptic terminal?

A

It closes Cav channels and decreases the release of neurotoxic glutamate.

60
Q

What happens when TREK1 opens on the postsynaptic terminal?

A

It hyperpolarize cell and increases NMDA receptor Mg2+ block-reducing excitotoxicity.

61
Q

What does Kir6.x form?

A

It forms, along with an additional regulatory subunit, the sulphonylurea receptor (SUR), a channel whose activity is inhibited by intracellular ATP (KATP channel). There are 2 gene products for both subunits (KIR6.1 AND 6.2; SUR 1 and 2) and various combinations provides diversity.

62
Q

Describe the action of KATP channels:

A

They act to couple cellular metabolism and electrical activity.

63
Q

What are the two functions provided by the action of KATP channel?

A

Stress sensing in skeleta, cardiac muscle and some neurons

Glucose sensing: pancreatic beta cells and certain neurons (eg. hypothalamus).

64
Q

Describe the action of KATP as stress sensors:

A

As stress sensors KATP channels are closed uner normal physiological conditions and open under metabolic stress (such as anoxia/hypoxia) due to ischemi or severe hypoglycemia.

65
Q

What does opening of Katp results in?

A

Hyperpolarisation of RMP. This allows metabolically compromised cells to rest/recover.

66
Q

Describe the action KATP in glucose-sensing cells:

A

Katp in glucose-sensing cells are partially open under physiological condition and contribute to the cell RMP. Increased glucose concentration increases intracellular intracellular ATP concetration and closes KATP.

67
Q

What does inhibition of KATP by increased glucose channels results in?

A

Cell depolarisation (e.g. in pancreatic beta cells increased glucose causes insulin secretion)

68
Q

Describe inhibitors of KATP channels:

A

Class of drugs called sulphonylureas are the best known. These include tolbutamide and glibenclamide and are used in the treatment of Type 2 diabetes mellitus.

69
Q

Describe activatros of KATP channels:

A

A wide range of drugs have been developed which act on KATP channels and are generally called Potassium Channel Openers (KCO)

70
Q

List four KCOs:

A

Comakalin, Pinacidil, Minoxidil, Diazoxide.

71
Q

Describ Diazoxide:

A

It is occasionally used to decrease insulin secretion from beta cells.

72
Q

Why has been the majority of KCOs developed?

A

The majority of KCOs have been developed to relax smooth muscle and many compounds are under development and testing for a variety of indications.

73
Q

What does the active form of GPCRs to K+ channels in cardiac muscle do?

A

Active form with GTP bound: G-proteins cause K+ channels to open.

74
Q

How is activity in GPCR terminated in cardiac muscle?

A

It is terminated by intrisic GTPase acvitiy of G-protein itself (converting GTP to GDP).

75
Q

Describe Cardiac: Long-QT syndrome associated with K+ channels.

A

inherited genetic disorder characterised by prolonged or delayed ventricular repolarisation. Associated with reduced function of certain voltage-gated K+ channel genes e.g. KCNQ1 & hERG and their associated accessory beta-subunits.

76
Q

Describe Epilepsy associated with K+ Channels:

A

certain forms of hereditary epilepsy associated with mutations leading to decreased expression/function of voltage-gated K+ channels (KCNQ 2 & KCNQ3).

77
Q

Describe neurodegeneration associated with K+ channels.

A

the mouse weaver disorder is similar to Parkinson’s disease - movement disorder - death of dopamine neurons associated with mutation of KIR3.2.

78
Q

Describe HI (hyperinsulinemia of infancy) associated with K+ channels:

A

both sporadic and hereditary disease where inappropriate enhanced insulin secretion occurs - leads to hypoglycaemia, coma and severe brain damage. Multiple mutations associated with KATP channel - both KIR6.2 & SUR1

79
Q

Describe diabetes associated with K+ channels:

A

activating mutations in KIR6.2 associated with decreased insulin secretion from pancreatic b-cells

Jacopo Biomembranes (16 decks)

Brainscape helps you reach your goals faster, through stronger study habits.
© 2024 Bold Learning Solutions. Terms and Conditions