PSC2002/L20 Calcium Signalling IV Flashcards
Give the 3 types of RyR receptor and where they are found.
Type I - skeletal muscle
Type II - cardiac muscle
Type III - brain
What is the difference between the 3 IP3 isoforms?
Different affinities for IP3 and calcium
CICR occurs at different times
What are the differences between receptor isoforms on different cells? (3)
Affinity
Stability
Cellular localisation
What is the signalsome?
Toolkit for calcium signalling in a specific cell
Includes specific isoforms involved in on/off mechanism
Give the 6 components of the calcium signalling toolkit.
Receptors
Transducers
Channels
Pumps
Buffers
Sensors
Describe a cardiac specific calcium signalsome.
ON - Et-1R, PLCbeta1, L-type; RYR2
OFF - SERCA2a, PV
Sensors - CAM, TnC
Describe a T cell-specific calcium signalsome.
ON - TCR; IL-2R, PLCy1; PI 3-K
OFF - SERCA2b, CR
Sensors - CAM
Define and give an example of phenotypic remodelling of the signalsome.
Txn rate increased or decreased
E.g., phosphorylation can change activity of a component; altered txn rate of component
Define and give an example of genotypic remodelling of the signalsome.
Change due to inherent event with protein
E.g., somatic mutations in single cells alters activity of component
Germline mutations passed from one generation to next
When does phenotypic remodelling occur?
Under normal conditions for normal operation of the cell
Describe phenotypic remodelling in the heart during exercise.
Increased force of contraction with exercise
cAMP-dependent reversible phosphorylation of key Ca2+ signalling components (e.g., VOC, SERCA) enables heart cells to generate larger Ca2+ signals
Increased L-type and SERCA2a
Describe phenotypic calcium remodelling in the liver during regeneration.
Down-regulation of key Ca2+ signalling components results in lower frequency Ca2+ spikes of greater duration
What kind of calcium remodelling is involved in:
a) Alzheimer’s Disease
b) Brody’s Disease?
a) phenotypic signalsome
b) genotypic signalsome
Describe the pathogenesis of Alzheimer’s Disease. (4)
Extracellular plaque deposits of B-amyloid disrupts synaptic transmission
AB increase Ca2+ entry via NMDA receptor
Amyloid precursor protein (APP) intracellular domain (AICD) increased Ca2+ release from stores
Upregulation of neuronal Ca2+ signalling to induce initial decline in memory
Give 3 binding sites on NMDA receptors.
Glycine site
Channel pore
Zinc site
Proton site
Glutamate site
Polyamine site
What is a NMDA receptor?
Non-specific cation channel
Large Ca2+ component
Describe the change in Ca2+ during Alzheimer’s pthogenesis. (2)
Overexpression of RyR so increase Ca2+ leak
Decrease in Ca2+ buffering through calbindin
What is the normal level of resting Ca2+ and what does this increase to during AD?
100nM to 300-500nM
Describe normal memory storage. How is this different in AD? (4)
Ca2+ entry through NMDA receptor
Memory formation (LTP) to temporary memory store
Memory consolidation into permanent memory store
Long term depression erases temporary memory store
Describe memory formation in AD. (2)
Long term depression occurs throughout so temporary memories erased before they become permanent
Amyloid metabolism enhances resting level of calcium
Give an alternative name for:
a) LTP
b) LTD.
a) memory storage
b) memory loss
Give a potential therapy for reversing Ca2+-dependent neurodegeneration.
Vitamin D3 acts as TF for many OFF mechanisms
Bringing down calcium baseline
Describe how onset and progression of AD can be described as positive feedback.
Ca2+ signalling stimulates metabolism of APP
Amyloidogenic pathway increases resting Ca2+
What is Brody’s Disease (myopathy)?
Skeletal muscle genetic disorder characterised by stiffness and cramp brought on by prolonged Ca2+ elevation and slowing of relaxation
How is Brody’s disease caused?
Defect results from mutation in SERCA1 pump
SR unable to refill with Ca2+
Cytosolic Ca2+ remains elevated so relaxation impeded
Give 2 examples of Ca2+ signal remodelling in cancerous cells.
Altered SERCA pump activity
Altered Ca2+ release through InsP3Rs
Altered resting level of Ca2+
What is the cause of cancer with relation to Ca2+?
Unknown whether Ca2+ signal remodelling is a consequence of cancer or helps to cause cancer
Due to bidirectional relationship between them
Describe the bidirectional relationship between Ca2+ signalling and cancer.
Ca2+ signalling remodelling causes changes in cellular activity
Cancer (changes to cellular activity) causes remodelling of Ca2+ signals
