Calcium Signalling Flashcards
(13 cards)
Calcium signalling
- calcium = both a first and second messenger
- resting calcium maintained by calcium ATPase and sodium/calcium exchanger
- SERCA pumps calcium into SR
Effects of calcium
effects of calcium with increasing time course
- exocytosis
- contraction
- metabolism
- transcription
- fertilisation
- proliferation + hypertrophy
SERCA isoforms
1 = skeletal, high pumping activity
2a = cardiac
2b = ubiquitous, slower than 2a
3 = specialised
Stimulation
- calcium entry via NMDARs, voltage-gated calcium channels and SR release
- calcium is not diffusible - acts locally with global effect
- doesn’t diffuse far from channel
- acts in restricted microdomains
- gradient of calcium from channel
ER as calcium store
- discovery of ER as the IP3 mobilisation store
- previously thought mitochondria was calcium store
IP3 = calcium puff
summate to form calcium transient
feed-forward
calcium oscillations manipulated by SERCA vs IP3
- both amplitude and frequency encode information
Intracellular channels
- RyR and IP3R are both receptor calcium channels
- localised to ER
- RyR associated with excitable cells
- IP3R associated with non-excitable cells, though high expression in neurones
- in skeletal muscle, voltage-gated calcium channels are mechanically coupled to RyR = calcium-induced calcium release
- IP3R calcium release promoted by IP3 produced by Gq or RTK activation
Membrane channels
- TRPs = transient receptor potential family
- identified first in Drosophila as responsible for phototransduction (mutant = blind)
- initially considered to replenish calcium stores in mammalian cells
- now have widely established roles in many aspects of cell function
Lysosomal store
- NAADP = highly potent agonist of calcium release
- CD38 = enzyme that generates NAADP
- downstream of many mediators such as AngII, catecholamines etc
- NAADP activates TPC2 to promote cation release from lysosomes
- can also crosstalk where calcium release through TPC2 can amplify by promoting ER calcium release
- so lysosomes are situated close to the ER
- sensitises RyR to calcium and IP3R to IP3 so more calcium release
Calcium clearance
calcium base level controlled to be low due to cytotoxic effects
- uptake into mitochondria
- reuptake into ER
- into Golgi by SPCA P-type ATPases
Calcium clearance - uptake into mitochondria
- IP3R close to mitochondria so its close enough to sense calcium
- at high calcium, gets taken up by mitochondria
- at low calcium, mitochondria has low levels of calcium uptake due to low affinity
mitochondrial uniporter
- low sensitivity to calcium
- MICU and MCU accessory proteins modulate sensitivity to calcium
Calcium clearance - uptake into ER
- refilling by store-operated calcium entry (SOCE) or capacitative calcium entry
- likened to situation in skeletal muscle hypothesised as conformational coupling
- defined by current-calcium release activated ICRAC = increased sensitivity and reduced conductance
Transcription
- calcium regulates contraction and transcription
- calmodulin switches between active and inactive state
- specificity determined by code readers
1. affinity for calcium (synaptotagmin>CaM)
2. sensitivity to calcium oscillation frequency
3. cellular location
CaMK as an integrator of calcium signals
- CaMK has a hexameric structure
- CaMKII particles = kinase domain positioning is highly variable
- on binding CaM, it undergoes autophosphorylation
- also subject to oxidation
- calcium changes are remembered by CaMK
