CaV Channels Flashcards
- List the subunits that assemble to form a voltage-gated Ca channel - List the subtypes and corresponding properties of CaV channels - Explain the importance and mechanism by which phosphorylation and G proteins regulate the Ca current from a CaV channel - Describe the clinical importance of Ca channels and list the channelopathies that may result from inherited mutations in CaV genes
1
Q
Functions of Ca channels
A
- regulate intracellular calcium concentration and contribute to calcium signalling
- mediate calcium entry into cells in response to depolarisaiton
- control AP generation and conduction
- control sensory processes
- control muscle contraction
- control secretion of transmitters and hormones
- control cell differentiation and gene expression
2
Q
What is the ionic requirement for release
A
- calcium influx = fast evoked transmitter release
- chemical signal carried by calcium is important, not the electrical charge
3
Q
Structure of Ca channel alpha subunits
A
- Four repeat domains
- 6 TM segments, membrane-associated loop between S5 and S6
- Glutamic acid residues in P regions are important for determining selectivity for calcium ions
- auxillary subunits
4
Q
Subtypes of calcoum channels
A
- some require large depolarisation to elicit opening (HVA) / L-type
- others open at more negative potentials (LVA) / T-type
- HVA display variable inactivation
- LVA display rapid voltage dependent inactivation
5
Q
L type calcium channel
A
- HVA
- Blocked CHPs
- E-C coupling, hormone secretion, muscle contraction
- most have all 5 subunits
6
Q
N type calcium channel
A
- HVA
- Blocked w-CTx* GVIA
- Neurotransmitter release
7
Q
P type calcium channel
A
- HVA
- blocked w-Aga * IVA (spider)
- Neurotransmitter release
8
Q
Q type calcium channel
A
- HVA
- Blocked w-CTx* MVIIC
- Neurotransmitter release
9
Q
R type calcium channel
A
- H/LVA
- Blocked SNX-482 (tarantula toxin)
- Ca-APs and neurotransmitter release
10
Q
T type calcium channel
A
- LVA
- Blocked Mibefradil
- repetitive firing
- structure unknown
11
Q
Molecular basis of calcium channel diversity
A
diversity of Ca channels arises from the combination of five subunits
12
Q
alpha1 subunit
A
- has basic Na channel alpha subunit structure
- 10 individual genes of these
13
Q
beta subunit
A
- 4 genes intracellularly located
- each alpha subunit is associated with multiple beta subunits
14
Q
alpha2 subunit
A
- highly glycosylated
- extracellularly locatedd
- attached to membrane through disulphide linkage to delta subunit
15
Q
delta subunit
A
anchors alpha2 complex to the alpha1 subunit via a single transmembrane segment
16
Q
alpha2delta complex
A
occurs as 4 seperate genes
17
Q
gamma subunit
A
- glycoprotein
- 4 transmembrane segments
- may be up to 8 genes involved
18
Q
Location of Cav1.1-4
A
- L type
- cardiac and skeletal muscle, neurons, and endocrine cells
19
Q
Location of Cav2.1
A
- P/Q type
- nerve terminals, dendrites
20
Q
Location of Cav2.2
A
- N type
- nerve terminals, dendrites
21
Q
Location of Cav2.3
A
- R type
- Cell bodies, nerve terminals, dendrites
22
Q
Location of Cav3.1-3
A
- T type
- cardiac and smooth muscle, neurons
23
Q
Describe the ‘mode-switching’ of L-type channels
A
- multiple gating kinetics
- during series of consecutive sweeps of depolarising pulses, see clusters of sweeps in 3 different kinetic modes
- Mode1 = normal short open times
- Mode0 - no openings
- Mode2 = long open times
24
Q
Function of Beta-adrenergic agonists
A
- increase cardiac AP amplitude, and muscle contractility and rate
- mimicked by increase of cAMP in cell
- PKA phosphorylates native beta subunits in cardiac tissue
- other protein kinases activated by hormones/transmitters likely modulate Ca channel activity
25
G-protein regulation of Cav2 family
- inhibits calcium current
- responsible for decrease in synaptic transmission as calcium entry at nerve terminal is reduced
- GBY dimer mimics agonist actions (tonic inhibition of calcium current)
- depolarisation reduces inhibitory effect
26
What are the major classes of drugs that act on L-type Ca channels
- Dihydropyridines (DHPs)
- Phenylalkylamines
- Benzothiazepines
- used therapeutically to treat hypertension, cardiac arrhythmias and ischemic heart disease
27
MoA of L-type Ca channel drugs
- block calcium influx by more than one mechanism
- dihydropyridines act as allosteric modulators, alter gating behaviour of L-type calcium channels
- DHP antagonists stabilise Mode0 behaviour
- DHP agonists increase Ca current by stabilising Mode2 behaviour
28
How do DHPs block L-type calcium channels
bind to specific sites within S5 and S6 segments of alpha subunit
29
How do Phenylalkylamines block L-type calcium channels
- use-dependent manner from intracellular side of membrane via open channel block
- bind to inner end of transmembrane pore (sites in S6 in domains III and IV)
30
How do benzothiazepines block L-type calcium channels
bind to residues in S5-S6 linker of domain IV
31
What is hypokalemic periodic paralysis type I caused by
Cav1.1 expressed specifically in skeletal muscle: mutations (S4 regions) result in reduced calcium current and muscle weakness
32
What is Timothy Syndrome caused by
- rare childhood multi-organ disorder - cardiac defects, immune deficiency, cognitive abnormalities, generally sporadic
- mutations in Cav1.2 cause loss of channel inactivation -> enhanced calcium entry -> severe cardiac dysregulation
33
What is night blindess caused by
- one form caused by decreased transmitter release from retinal photoreceptor terminals
- mutiple mutations associated with loss of function of Cav1.4
34
What is a migraine caused by
- mutations of the Cav2.1 gene causing increased channel activity and transmitter release
35
What is Episodic Ataxia Type II caused by
- recurrent attacks of motor dysfunction
- disruption of Cav2.1 gene
- preventing formation of normal functional channels
- loss of calcium current
36
What is epilepsy caused by
- mutations in calcium channel auxillary subunits
- alter P/Q channel function
37
What is autism spectrum disorder caused by
mutations in Cav3.2 (T-type), reduce channel activity
