Name the 3 physiological functions that the potassium channels contribute to?
1. Control of cell volume. 2. Control of membrane potential and cell excitability. 3. Secretion of salts, hormones & neurotransmitters.
Name the 5 regulators of the potassium channels activity?
1. Numerous hormones & transmitters. 2. Voltage across membrane. 3. Conc. of calcium or ATP in cytoplasm. 4. Kinases and phophatases. 5. G-proteins
Name the 3 structures of the potassium channels?
1. 6 transmembrane one-pore 2. Two transmembrane one-pore 3. Four transmembrane two-pore
Properties of the 6-transmembrane segment potassium channels?
1. alpha subunit similar in shape to the sodium and calcium channels. 2. Contains S4 voltage sensor and P region.
Name the four channels that are part of the 6-transmembrane segment family?
1. hERG channels. 2. Voltage-activated potassium channels. 3. Calcium activated potassium channels. 4. KCNQ channels
What is the role of the voltage-activated potassium channels?
Responsible for shaping of the action potential.
Name the main two types of voltage-activated potassium channels?
1. Inactivating 'A' type. 2. Non-inactivating
Properties of the inactivating 'A' type of voltage-activated potassium channels?
Display rapid inactivation following opening. Ball and chain form of inactivation
Properties of the non-inactivating type of voltage-activated potassium channels?
Slow inactivation.
Describe the "ball and chain" form of inactivation?
First 20 amino acids forms compact hydrophobic charged surface domains which plugs the channel from the inside. Prevents potassium efflux
Describe the properties of the N-type inactivation?
Ball and chain inactivation mechanism.
Where is the ball made from the ball and chain inactivation?
Set of amino acids in the S4-S5 loop.
What controls the activity of the potassium channel?
Controlled by the conc. of cytoplasmic calcium. Important in limiting calcium entry and neuronal excitability.
Name the 3 subtypes of calcium-activated potassium channels?
1. Large conductance (maxi-K) 2. Intermediate (IK) conductance. 3. Small (SK) conductance.
What channel is important for the slow afterhyperpolarisation observed after AP discharge?
Small conductance channels are responsible for this.
Where are maxi-K channels expressed?
Ubiquitously (found everywhere) Help shape APs in neurones and regulate transmitter release. In smooth muscle: regulate contractile activity and tone.
What controls the opening of maxi-K channels?
Transmembrane voltage as they are voltage-dependent.
What is the activation of maxi-K channels dependent on?
The intracellular calcium conc. The more calcium conc. in the cell: the less electrical energy is needed to open it.
Describe the beta and alpha subunits of the maxi-K channel?
beta: 2 transmembrane domians. Alpha: 6.
What part of the alpha subunit is important for the function of the maxi-k channel?
The long COOH terminus
What gene encodes for the Maxi-K alpha subunit?
Slo gene.
What part is unique to maxi-K channels?
SO region
Name the 4 types of beta subunits?
b1-4
Role of the beta subunits in the maxi-K channel?
Alter sensitivity to calcium and voltage, activation kinetics.
What terminal is required for beta subunit modulation?
S0/N terminal
Where are maxi-K channels most abundant?
In CNS and smooth muscle.
Name the two forms of gating for the maxi-K channel?
Voltage-gating and ligand-gating domains. 2 independent sensing mechanisms
What part of the channel acts as the voltage sensor?
S4 region
What part of the channel acts as the ligand gating?
Specialised structures present in the C-terminal region of the protein
Define the role of the RCK domain?
Regulators of conductance of potassium. Contribute to binding of intracellular ligand
Name the hydrophilic domains?
S9 and 10 of the COOH tail.
What part of the COOH tail binds calcium?
Calcium bowl. Contains a series of negatively charged residues.
What part of the COOH tail senses voltage?
S7 and 8 domain (RCK)
How does the calcium bowl help in the calcium sensing of the maxi-K channels?
Calcium bowl interacts with the RCK domain to confer calcium sensing.
How to increase the probability of the maxi-K channel opening?
Increasing intracellular calcium increases the opening force (calcium bowl + RCK domain). Voltage sensor adds to this force on the gates (S4 domain) and increases channel open probability.
Loss of beta 1 subunit of the maxi-K correlates with what?
hypertension. Maxi-K is less calcium sensitive- increased arterial tone and BP.
Maxi-K channels importance in VSM relaxation?
Calcium released by receptors causes local increase in calcium conc. Activates BK channels- K efflux. Hyperpolarisation: Initial depolarisation and contraction. Vascular smooth muscle relaxes.
Maxi-K channels importance in neuronal excitability?
Present at high levels in axon terminals, somas and dendrites. Activated by increased intracellular calcium- profoundly depresses excitability.
Properties of the two transmembrane domain potassium channels?
One pore family. Consist of the inward rectifiers. Conduct potassium current more in the inward direction than the outward. Help set RMP
Properties of the four transmembrane domain potassium channels?
Two pore family. Weak inward rectifiers. Most abundant class. Act as background channels. Help set RMP.
How many subunits are needed to form a functional channel of TREK1?
Only need 2 subunits. As they contain two 'P' loops
K2p channel opening properties?
Constitutively open at rest. Contribute to RMP.
Name the factors that control TREK1 channel activity?
Numerous cellular factors such as voltage.
The role TREK1 plays in the body?
Neuronal background channel. Single integrators- response to many inputs mechanical deformation.
How do you inhibit TREK1 channels opening?
Through phosphoryation at intracellular sites via PKC and PKA.
Name the two types of anaesthetic agents that open TREK1?
Various volatile and gaseous anaesthetics agents.
Where are the TREK1 channels expressed in within the body?
Highly expressed in the brain.
Name the 5 different stimuli used to open the TREK1 channel?
1. Pressure 2. Heat 3. Voltage 4. Anaesthetics and lipids. 5. pH
Name the 3 different developmental areas that TREK1 is an attractive target for?
1. New analgesics. 2. Neuroprotective agents. 3. Antidepressant drugs.
Name the 4 openers of TREK1?
1. Anaesthetics 2. Polyunsaturated fatty acids. 3. Lysophospholipids. 4. Riluzole.
What happens in the presynaptics terminals when TREK1 channels are opened?
Closes voltage activated calcium channels. Decreasing the release of neurotoxic glutamate.
What happens in the postsynaptics terminals when TREK1 channels are opened?
Hyperpolarises cell and increases NMDA receptor. Magnesium is used to block the channel- reducing excitotoxicity.
Properties of the Kir 6.x channel?
Part of the K ir family of channels. This + a regulatory subunit = the SUR receptor. Activity inhibited by intracellular ATP.
Name the two genes that encode for the Kir 6.x channel?
Kir 6.1 and Kir 6.2
Role of the K atp channels?
Act to couple cellular metabolism and electrical activity. Responds to ATP levels
Name the two functions of the K ATP channels?
1. Stress sensing eg. skeletal, cardiac 2. Glucose sensing eg. pancreatic b-cells
What happens to the K ATP channel when the ATP level is high?
The level of ATP is high inside the cell. Receptor closes.
What happens to the K ATP channel when the ATP level is low?
The receptor opens.
How does the K ATP channel work as a stress sensor?
These channels are closed under normal physiological conditions. Opens under metabolic stress (eg. hypoglycemia)
What happens to the RMP when K ATP channels are open ?
Results in hyper polarisation of the RMP.
How does the K ATP channel work as a glucose-sensor?
In these glucose-sensing cells the K ATP channels are partially open under physiological conditions and contribute to the RMP. Increase in glucose conc. increases intracellular ATP conc. and closes these channels. Results: increase in glucose conc. = cell depolarisation.
Describe how the beta cells are at rest?
K ATP channels are open and the cell is at RMP. Low glucose levels outside: low ATP inside the cell: KATP channel open: Voltage gated calcium channels open: no insulin release.
Describe what happens to the beta cells when there is an increase in glucose extracellularly?
GLUT transporter transports the glucose inside the cell. Increase in ATP- KATP channels closed- cell depolarisation- voltage gated calcium channels open- insulin released
Describe the properties of the inhibitors of KATP channels?
Sylphonylureas. Increase tolbutamide and glibenchamide
Sylphonylureas use?
As inhibitors of the KATP channels. Blockers
Describe the properties of the activators of KATP channels?
Act on these channels to open them. Termed as potassium channel openers (KCOs) eg, cromakalim, pinacidil, minoxidil and diazoxide
Use of diazoxide?
Used to decrease insulin secretion from beta-cells
Use of the majority of KCOs?
Used to relax smooth muscle and testing for a variety of conditions such as hypertension, bladder overactivity. Also useful as cardioprotective and neuroprotective agents
How does the G-protein couple to K channels?
Directly. G-proteins bind to the muscarinic ACh receptor and thus opens the potassium channels
Properties of Long-QT syndrome?
Inherited genetic disorder. Characterised by prolonged or delayed ventricular repolarisation. Reduced function of certain voltage-gated potassium channel genes.
Properties of epilepsy with respects to potassium channels?
Mutations leading to decreased expression/function of voltage-gated potassium channels.
Properties of neurodegenerative conditions with respects to potassium channels?
Mutations in the Kir 3.2 Death of dopamine neurones.
Properties of hyperinsulinemia of infancy?
Enhanced insulin secretion occurs. Leads to hypoglycaemia, coma and severe brain damage. Multiple mutations associated with K ATP channel
Properties of diabetes (Type 2)?
Activating mutations in Kir 6.2 with decreased insulin secretion from pancreatic beta cells.
Describe the cardiac action potential?
Stage 4: resting at -96mV. Stage 0: sodium in rapidly. Stage 1: potassium and chlorine out Stage 2: calcium in, potassium out Stage 3: potassium out.
