What is the function of the voltage-activated calcium channels?
Regulate intracellular calcium conc. and contribute to calcium signalling.
What do the voltage-activated calcium channels mediate?
Calcium entry into cells in response to depolarisation.,
Name the 5 different cellular events that voltage-activated calcium channels control?
- AP generation and conduction.
- Sensory processes.
- Muscle contraction
- Secretion of transmitters and hormones.
- Cell differentiation and gene expression.
Name the 4 different modulators of calcium channels?
- Hormones.
- Transmitters
- Protein kinases.
- Phosphatases.
What is associated with spontaneous mutations of calcium channels?
Hyperexitable disorders.
What is triggered by calcium influx?
Fast evoked transmitter release.
Elevation of intracellular calcium conc. is an absolute requirement for transmitter release.
What signal is the important factor when calcium enters the cell?
The chemical signal.
The calcium itself is necessary not the charge that comes with it.
How many domains does the calcium channel have?
4 repeat domains.
How many transmembrane segments are in each domain?
6 transmembrane domains.
Where is the membrane-associated loop in the calcium channel?
Between S5 and S6.
What is the importance of the glutamic acid residue in the P regions of each domain?
Important in determining the selectivity for calcium ions.
How are the calcium channels subdivided?
On the basis of the voltage-required to activate them.
Name the 2 subtypes of calcium channels?
- High-voltage activated calcium channels (HVA)
2. Low-voltage activated calcium channels (LVA)
What are the properties of the HVA calcium channels?
Require a large depolarisation (-20mV) to elicit opening.
Display variable inactivation
What are the properties of the LVA calcium channels?
The calcium channels in this group open at a much more negative potential (-50mV)
Generally display rapid voltage dependent inactivation.
What are the other names given to the HVA and LVA? and why is that?
HVA channels are also called L-type. They are long-lasting.
LVA channels are also called T-type (transient). They display fast voltage-dependent inactivation
Name the 6 different subtypes of calcium channels?
- L-type; long-lasting
- T-type; transient
- N-type; neuronal.
- P-type; purkinje cell.
- Q-type; cerebellar granule neurones.
- R-type; resistant component.
Where are the L- and T-type calcium channels found in the body?
In a wide range of cells.
Where are the N-, P-, Q- and R-type calcium channels found in the body?
Mostly found in neurones.
Describe the properties of the L-type calcium channel?
HVA.
Blocked by dihydropyridines
Important in hormone secretion.
Describe the properties of the N-type calcium channel?
HVA.
Blocked by conotoxin
Important in the neurotransmitter release.
Describe the properties of the P-type calcium channel?
HVA
Blocked of the agatoxin.
Important in the neurotransmitter release.
Describe the properties of the Q-type calcium channel?
HVA
Blocked by conotoxin.
Important in neurotransmitter release.
Describe the properties of the R-type calcium channel?
H/LVA
Blocked by tarantula toxin.
Important in the action potential process.
Describe the properties of the T-type calcium channel?
LVA
Blocked by mibefradil.
Important in repetitive firing.
What is the reason for the diversity of calcium channels?
Arises from the combination of five subunits.
Describe the properties of the alpha 1 subunit of the calcium channel?
The basic sodium channel a subunit structure.
Appear to be 10 genes that code them.
Describe the properties of the beta subunit of the calcium channel?
Intracellularly located.
4 genes that code them.
Each subunit is associated with multiple beta subunits.
Describe the properties of the alpha 2 subunit of the calcium channel?
Extracellularly located.
Attached to the membrane through disulphide linkage to a delta subunit.
Properties of the delta subunit of the calcium channel?
Linked with the alpha 2 subunit through disulphide linkage.
Anchors the complex to the alpha 1 subunit via single transmembrane segment.
How many genes code for this alpha 2: delta subunit?
4 separate genes.
Properties of the gamma subunit of the calcium channel?
A glycoprotein.
4 Transmembrane segments
Up to 8 genes involved.
How many subunits does the L-type channel have?
All 5 subunits.
Describe the properties of the calcium voltage dependent channel 1.1, 1.2, 1.3 and 1.4?
Current type: L
Location: cardiac, skeletal muscle, neurones and endocrine cells.
Describe the properties of the calcium voltage dependent channel 2.1?
Current type: P/Q
Location: nerve terminals, dendrites
Describe the properties of the calcium voltage dependent channel 2.2?
Current type: N
Location: nerve terminals, dendrites
Describe the properties of the calcium voltage dependent channel 2.3?
Current type: R
Location: cell bodies, nerve terminals and dendrites
Describe the properties of the calcium voltage dependent channel 3.1, 3.2 and 3.3?
Current type: T
Location: cardiac, smooth muscle and neurones.
Name the 3 different modes that the L-type calcium channel can display?
Mode-switiching- multiple gating kinetics.
- MODE 1: normal short open times.
- MODE 0: no openings.
- MODE 2: long open times
What modulates the L-type calcium channels?
By hormones and neurotransmitters in muscle and neurones.
What does the beta-adrenergic agonist do?
Increase cardiac AP amplitude
Muscle contractility and rate.
Does this by shifting the gating of the L-type channel or by opening more calcium channels.
What happens the adrenergic is stimulated?
Increase probability of opening the calcium channel.
Increases the apparent number of functional calcium channels.
What mimics the adrenergic stimulation?
Increase of cAMP in the cell
How does cAMP mediate an increase in calcium current?
cAMP-dependent protein kinase A (PKA) phosphorylates a subunit on the calcium 1.2 channel to increase the calcium current.
When a beta-subunit is present what happens when b-adrenergic agonist is present?
Enhances the agonist activation of the calcium 1.2 channel.
What is coupled to calcium channels N, P/Q?
GPCRs.
The role the GPCRs play in the N, P/Q calcium channels function?
Inhibits calcium current- causes a decrease in synaptic transmission.
Gby dimer role in the regulation of calcium 2 family by G-proteins?
Mimics agonist actions-tonic inhibition of calcium current.
Name the 3 major classes of drugs that act on L-type calcium channels?
- Dihydropyridines.
- Phenylalkylamines.
- Benzothiazepines.
Why are the drugs that affect L-type calcium channels clinically relevant?
Used therapeutically to treat hypertension, cardiac arrhythmias and ischaemic heart disease.
How do the drugs act on the L-type calcium channel?
Act to block calcium influx.
DHP: act as allosteric modulators- alter the gating behaviour.
DHP antagonists: act to stabilise mode 0 behaviour.
What does the agonist do to the mode of the L-type calcium channel?
Changes it from MODE1 to MODE2.
What does the antagonist do to the mode of the L-type calcium channel?
Changes it from the MODE1 to MODE0
Where does the DHPs bind to the calcium channel?
At the S5-6 segment on the alpha subunit
Properties of the phyenylalkylamines?
Blocks L-type calcium channels in a use-dependent manner.
Blocks from the intracellular side.
Properties of the benzothiazepines?
Act extracellularly.
Binding to residues in S5-6 of the 4th domain
What tissue are N, P/Q and R type calcium channels associated with?
Peripheral and CNS
What tissue is the T-type calcium channel associated with?
Cariovascular and neuronal tissues
What medical conditions are associated with neuronal calcium channels?
Epilepsy and pain.
Function of ziconotide?
Drug used to treat chronic neuropathic pain.
Peptide toxin that interacts with N-type calcium channel.
Function of gabapentin/pregabalin?
Used to treat chronic pain through their interactions at the alpha 2 delta subunit.
Describe hypokalemic periodic paralysis?
Calcium 1.1 channel mutation in the S4 regions cause a reduced calcium current and muscle weakness
Describe timothy syndrome?
A rare childhood multi-organ disorder.
Mutations in the calcium 1.2 channel.
Loss of channel inactivation.
Describe night blindness?
Loss of function of calcium 1.4 channel.
Describe the cause of migraine?
Associated with mutations of the calcium 2.1 channel.
Causing increased channel activity and transmitter release.
Describe the cause of ataxia type 2?
Disruption of the calcium 2.1 gene.
Loss of calcium current.
Describe the cause of epilepsy?
Mutations in the calcium channel auxiliary subunits associated with certain forms of epilepsy.
Describe the cause of the autism spectrum disorder?
Mutations in the calcium 3.2 channel.
Reduce channel activity