lecture 19 Flashcards
heterogeneity
each component can have multiple isoforms
e.g. there are 3 different isoforms of the IP3 and RyR receptors
some isoforms are less sensitive to IP3 for example
for some the calcium channel stays open for longer
cell specific calcium signalsome
defines the precise isoform of that specific toolkit component that is in any given cell type
signalsomes can be remodeled (altered)
2 types of remodeleing
1. phenotypic remodelling
when a component becomes phosphorylated
alters transcription rate so more/less of it is produced
genotypic remodelling - mutation in the gene that is encoding to isoform - alters the activity
if mutation occurs in the germline cells (ovaries of testes) the mutation will be passed down onto the next generation
phenotypic remodelling in normal cells example
heart - increased force of contraction with exercise
adrenaline binds to its receptors in the heart cells that elevates cAMP which causes phosphorylation of key calcium signalling components (voltage operated L-type calcium channel (VOC) and SERCA (off mechanism)) causes larger calcium transient, heart cells have a stronger contraction
phenotypic remodelling in normal cells example
liver - calcium signalling altered during regeneration
if liver gets damaged the liver will regenerate itself
down regulation of key Ca signalling components results in lower frequency Ca spikes of greater duration
has lower numbers of vasopressin 1 receptors and IP3 receptor whilst regenerating so calcium spikes are broader and less frequent
phenotypic and genotypic remodelling can alter the behaviour of cells so that their normal functions are subverted leading to disease
e.g Alzheimer’s disease (phenotypic modification)
brodys disease (genotypic modification)
Alzheimer’s disease (AD)
extracellular plaque deposits of the beta-amyloid peptide (Abeta) disrupt synaptic transmission
beta-amyloid oligemers increase calcium entry via the NMDA receptor
the amyloid precursor protein (APP) intracellular domain (AICD) increases calcium release from stores
this abnormal amyloid metabolism results in an upregulation of neuronal calcium signalling to induce an initial decline in memory
amyloid precursor protein is in the membrane and in AD the Abeta monomers come together into oligomer and the oligomer binds to the NMDA receptors allowing more calcium to enter the cell
also the AICD on the precursor protein gets chopped off into the cytosol and enters the nucleus where it is a transcription factor and it increases the transcription of RyRa and decreases the transcription of calbindin (buffer)
we get increased calcium leak through the RyR into the cytosol
calcium conc in the nervous cells increases
memory (normal)
are memories are triggered by calcium entry (1000nM) through the NMDA receptor which is known as LTP (long term potentiation)
when memories enter initially they enter the temporary memory store
overnight all those memories get consolidated into permanent memory store
once that has occurred we get a broader calcium signal (300nM) which triggers LTD (long term depression) which erases the temporary memory store so it can receive new temporary memories
memory (AD)
increased resting level of calcium due to amyloid (100nM to 300-500nM)
we still get LTP laying down the temporary memory
because the resting level is increased to 300-500nM we have persistent activation of LTD
this causes the erasure of the temporary memory store before the memories can be consolidated into the permanent memory store
explains why sufferers can remember stuff from a long time ago that were stored before the disease but their short term memory is gone
reversing this remodelling of calcium
we could try an increase the expression/efficacy of the off mechanisms
vitamin D does this. increases the expression of the plasma membrane calcium ATPases, sodium calcium exchanger and increases concentration of calbindin
there is a bidirectional relationship between calcium signalling and the amyloidogenic pathway
while the amyloids stimulate an increase in calcium, the calcium signalling stimulates the metabolism of APP
difficult to see what the initial problem is
genotypic remodelling can cause brody disease
skeletal muscle genetic disorder characterised by stiffnedd and cramp brought on by prolonger calcium elevation and a slowing of relaxtion
defect reaults from mutation in SERCA1 pump so it cannot pump all the calcium out the muscle and will leave residual calcium so muscles feel stiff
SR unable to refill with calcium, cytosolic calcium remains elevates so relaxation impeded
cancer (phenotypic and genotypic remodelling)
in cancer cells:
altered SERCA pump activity
altered calcium release through IP3Rs
altered resting level of calcium
whether calcium signal remodelling causes cancer or its a consequence is unknown as there is a bidirectional relationship
