lecture 20 Flashcards
what is heterogeneity?
the concept of diversity
what is desensitisation?
decreased ability of a receptor to respond to stimulation by a drug or ligand
what are isoforms?
-carry out same function but subtle differences
-eg. affinity, may be active for different lengths of time
-leads to output response subtly varying
what process occurs during development?
-signalsome expression
what is signalsome expression?
-appearance of cell type-specific signalsomes to create normal output signals used to control particular cellular functions
what happens during development of the cell in Ca2+ signalling?
different cells emit different Ca2+ signalling and different functions in those cells
what are the two subgroups in the expression?
- cardiac specific calcium signalsome (seen in contraction and gene transcription)
- T cell specific calcium signalsome (seen in gene transcription)
what are the receptors, transducers, channels, pumps, buffers and sensors for cardiac?
receptor = Et-1R
transducer = PLCb1
channel = L type RyR2
pumps = SERCA 2a
buffers = PV
sensors = CAM (calmodulin), TnC
what are the receptors, transducers, channels, pumps, buffers and sensors for T cell?
receptor = TCR, IL-2R
transducer = PLCy1, PI 3K
channel = Orai1, IP3, R1
pumps = SERCA 2b
buffers = CR
sensors = CAM (calmodulin)
how can signalsomes be remodelled?
-phenotypically
-genotypically
how are signalsomes remodelled phenotypically?
phosphorylation changing the activity, altered transcription rate
how are signalsomes remodelled genotypically?
somatic mutations in single cells altering activity, germline mutations passed on through generations
what occurs after remodelling
signal output is either reduced or increased
what is an example of phenotypic remodelling in the body?
heart -> increase force of contraction with exercise
1. adrenaline activates cAMP pathway in heart muscle
2. results in phosphorylation of key Ca2+ signalling components-the ON mechanism (SERCA pump and L type channel)- more Ca2+ enters cell
3. heart generates larger Ca2+ signals = more contraction = larger calcium transient = supports extra blood flow
what does phosphorylation of SERCA 2a pump lead to?
-speeds up pump
-can remove additional calcium
what is another example of phenotypic remodelling in the body?
liver -> calcium signal altered during regeneration of liver
-tested in rats
-down-regulation of the key Ca2+ signalling components results in a lower frequency Ca2+ spikes of greater duration
how does this happen in the liver?
- mutations in the different receptors in the G0/G1, S, M phases of interphase
- this shows the cell cycle progression - H0/H4 receptors are broad allowing more calcium to come causing more calcium spikes
- D5 and H24 - displays the calcium levels to be low as calcium channel shape is back to normal
what is Alzheimers disease caused by?
-extracellular plaque deposits of beta-amyloid peptide (Beta) which prevents synaptic transmission
-beta-amyloid proteins increase Ca2+ entry into neuronal cells - activate NMDA receptor
-more calcium entry and more calcium release
what does the amyloid precursor protein (APP) intracellular domain do?
increases Ca2+ release from stores (the ER)
what does the abnormal mechanism result in?
-upregulation of neuronal Ca2+ signalling
-induces initial decline in memory
how does this happen?
- metabolism of APP is slow, produces beta amyloid monomers
2.come together to form oligomers - these bind to the NMDA receptor and allow Ca2+ ions into the cell
- release amyloid precursor protein intracellular domain (AICD) into cell- transcription factor - alters rate of transcription of calcium signalling components eg. RyR
- activity of Ryanidine receptors increased
- more Ca2+ ions out ER into cytosol
- AICD decreases expression of calbindin so less buffering occurs
- resting level of calcium in cell increases
what is function of the amyloid precursor protein (APP)?
form synapses
what is the end result of this process?
amyloid-dependent up regulation of Ca2+ signalling
how does this contribute to memory in normal conditions?
- constant ca2+ entry through NMDA receptor - known as long term potentiation (LTP)
- memories held in temporary memory stores during day
- overnight, memory consolidation occurs where temp moves to permanent memory store
- towards end of process, NMDA activated again, smaller signal given triggering long term depression (LTD)
- LTD erases temporary memory store
how does this contribute to memory in people with Alzheimers?
- increased level of resting Ca2+ of 300-500nM
- cells try to fire NMDA receptors in LTP to make memories but LTD is permanently activated
- erasure of temporary memory store all of the time
- no memory consolidation occurs overnight -causes decline in short term memory
what does remodelling of Ca2+ signalling in Alzheimers disease cause?
switches brain from system of memory storage (LTP) to memory loss (LTD)
how might you reverse the effect of Alzheimers?
-try reduce elevated resting Ca2+
-Vitamin D3 acts as transcription factor for calcium OFF mechanisms
how does vitamin D3 work to reduce Ca2+ levels in alzhiemers?
- binds to VDR causing upregulation of PMCA, NCX1 and calbindin
- allows Ca2+ levels to be lowered, buffered
what is the positive feedback loop in Alzheimers?
- when amyloid metabolism goes wrong, increases Ca2+ levels
- this is then feeded back to stimulate metabolism of APP (increases Ca2+ resting level)
- positive feedback and makes it very hard to determine the primary cause of AD
what is the bidirectional relationship between?
Ca2+ signalling and amyloidogenic pathway
- amyloid stimulates increase, metabolism of APP stimulated
what is an example of genotypic remodelling?
Brody disease (Brody myopathy)
what is Brody disease?
-skeletal muscle genetic disorder
-characterised by stiffness and cramp
how is Brodys disease caused?
-by prolonged Ca2+ elevation and slowing of relaxation
-mutation in SERCA 1 pump = Ca2+ isn’t pumped back into SR from cytosol
-resting level elevated, low muscle contraction constantly activated (cramps)- relaxation cant occur
how does phenotypic and genotypic remodelling of Ca2+ happen in Cancer?
-altered SERCA pump activity
-altered resting levels of CA2+
-altered Ca2+ release through InsP3Rs
how is there a bidirectional relationship between cancer and Ca2+ signalling?
-remodelling of Ca2+ signals causes changes in cellular activity = cancer
-changes in cellular activity (cancer) causes remodelling of Ca2+ signals
