Calcium Channels Flashcards
(27 cards)
In normal Ca homeostasis how does calcium get in and out of the cell?
Ca2+ channels and Ca2+ permeable cation channels let calcium into the cell. Ca2+ pumps and Ca2+ exchangers let calcium out.
What should the concentrations of Ca on either side of the membrane be like normally?
There should be an internal concentration of around 100nM and an external concentration of 1mM.
Which organelle is important for calcium buffering within synapses?
Mitochondria
Trafficked into the synapse then buffer/act as stores
What is a calcium microdomain?
when the calcium concentration is higher closer to a channel.
Distance from the channel = sensitivity to Ca2+.
What is the relationship between nerve stimulation, Ca2+-influx and vesicular exocytosis?
They are tightly coupled together, allowing this process to be very rapid
Is the amount of neurotransmitter released per action potential constant?
No
Despite the quantal nature of release,
What is Facilitation of calcium?
Progressive increase in release due to residual calcium at release site during a train of action potentials (short lasting)
What is potentiation of calcium?
Variant of facilitation. Increase following repetitive (tetanic) stimulation.
Termed PTP, long lasting, involves mitochondrial calcium buffering and release.
Build up of calcium within stores.
What is depression?
Progressive decrease in release during a train of action potentials due to decline in readily releasable vesicle pool. Action potential overwhelms recycling process.
What do voltage sensitive/gated/dependent calcium channels do?
They mediate calcium influx in response to membrane depolarisation.
They couple electrical activity to neurophysiological events such as neurotransmitter release.
What is the structure of the voltage sensitive/gated/dependent calcium channel?
They are complex proteins with 4 to 5 different subunits (α1 and auxiliary) encoded by multiple genes, in the same family as voltage gated sodium channels and has a similar structure.
What is the evolutionary relationship between Na, K, and Ca channels like?
Very close
Common ancestor is NaChBac, the bacterial voltage-gated sodium channel.
What is the structure of the calcium channel α1 subunit?
Has 10 genes and is 190 – 250 kDa.
It contains conduction pore, voltage sensing and gating and majority of second messenger and toxin regulatory sites.
There are 4 homologous domains (I – IV), with 6 membrane segments in each (S1-S6).
Describe the membrane segments of the 4 homologous domains of the calcium channel
S4 is a voltage sensor, S5-S6 pore loop determines ion conductance.
3 amino acid changes in I, III, IV convert Na+ to Ca2+
What are the 4 types of high voltage activated VGCCs?
- L-type - Long lasting, slowly inactivating currents (>500ms). Calcium signalling channel – not linked to vesicles
- N-type - Neuronal, slowly inactivating
- P/Q-type - Purkinje, P slowly inactivating, Q variable
- R-type (IVA) – R (follows Q, Resistant) – slow / medium inactivation
What is the type of low voltage activated VGCCs?
T-type – Transient, rapidly inactivating
Which sites can be used to facilitate and inactivate VGIC?
The many phosphorylation sites on on α1 and a calmodulin binding domain near the C-terminus
_ binding facilitates and inactivates VSCC
Calmodulin
Affect of calmodulin on VSCCs
Different areas of the molecule will respond to different concentrations of Ca2+, very high levels will cause inactivation.
There is positive regulation of Cav2.1 in response to local Ca2+ increases (CDF) and negative regulation during more global Ca2+ increases (CDI).
What do the β subunits of VSCC do? (3)
They facilitate the correct folding and promote exit from the ER.
They also enhance Cav1 and Cav2 receptor trafficking.
Phosphorylation of β2 subunits via PI3K/Akt reduces channel degradation.
How many genes encode the α2δ and β subunits?
4 each
α2δ = single gene product post translationally cleaved
What does the α2δ subunit do?
The subunits enhance channel expression, trafficking and influence ion channel properties.
It is also site of binding for the anti-epileptic and anti allodynic drugs gabapentin and pregabalin
What is heterosynaptic plasticity?
It involves the modulation of presynaptic neurotransmitter release.
Autoreceptors like GPCRs detect the neurotransmitter itself (GABA B, mGluR II/III (Gi/Go coupled)).
Retrograde messengers are diffusible second messengers that are produced in target cell and diffuse back to nerve terminal (NO will enhance further neurotransmitter release).
What are retrograde messengers?
Diffusible second messengers which are produced by the target cell and diffuse back to control transmitter release in the nerve terminal
