L20 Ca2+ signal dysfunction in disease

what are the types of IP3 receptor

IP3 1,2,3 receptors

what are the types of RyRs

1,2,3 RyRs

during development what results in the appearance of cell type-specific signalsomes

signalsome expression

what do signalsomes create

normal output signals used to control particular cellular functions

what are the receptors for the cardiac -specific calcium signalsome

Et- 1R

what are the transducers for the cardiac -specific calcium signalsome

PLCbeta1

what are the channels for the cardiac -specific calcium signalsome

L-type; RyR2

what are the pumps for the cardiac -specific calcium signalsome

SERCA2a

what are the buffers for the cardiac -specific calcium signalsome

PV

what are the sensors for the cardiac -specific calcium signalsome

CAM, TnC

what are the receptors for the T-cell specific calcium signalsome

TCR; IL-2R

what are the transducers for the T-cell specific calcium signalsome

PLCgamma1: PI 3-K

what are the channels for the T-cell specific calcium signalsome

Orai: IP3 R1

what are the pumps for the T-cell specific calcium signalsome

SERCA2b

what are the buffers for the T-cell specific calcium signalsome

CR (calreticulim)

what are the sensors for the T-cell specific calcium signalsome

CAM (calmodulin)

how fast is the calcium transient (response) from a cardiac-specific calcium signalsome

1 second

what does a cardiac-specific calcium signalsome lead to

• contraction

• gene transcription

how fast is the calcium transient (response) from a T cell-specific calcium signalsome

100 seconds

what does the T cell-specific calcium signalsome lead to

gene transcription

signalsomes are not fixed in stone, but can be…

remodelled during both normal and pathological disease conditions

what are the 2 types of remodelling that can occur

• phenotypic remodelling of the signalsome

• genotypic remodelling of the signalsome

give an example of phenotypic remodelling of the signalsome

phosphorylation can change the activity of a component

• altered transcription rate of component

give an example of genotypic remodelling of the signalsome

somatic mutations in single cells alters activity of a component

• germline mutations are passed on from one generation to the next

remodelled signalsomes can have a reduced or elevated…

signal output

phenotypic remodelling occurs under normal conditions for the…

normal operation of the cell

give 2 examples of where phenotypic remodelling occurs under normal conditions

• heart

• liver

explain how increased force of contraction with exercise in the heart is an example of phenotypic remodelling under normal conditions

cAMP-dependent reversible phosphorylation of key Ca2+ components (e.g. VIC, SERCA) enables heart cells to generate larger Ca2+ signals

explain how calcium signalling in the liver being altered during regeneration is an example of phenotypic remodelling under normal conditions

down-regulation of key Ca2+ signalling components results in lower frequency Ca2+ spikes of greater duration

phenotypic and genotypic remodelling can alter the behaviour of cells so that their normal functions are…

subverted, leading to disease

in Alzheimer’s disease explain phenotypic remodelling by what do extracellular plaque deposits, of the beta-amyloid peptide (Abeta), disrupt

synaptic transmission

in Alzheimer’s disease explain phenotypic remodelling by what to beta-amyloid oligomers increase Ca2+ entry via

the NMDA receptor

in Alzheimer’s disease explain phenotypic remodelling by what does the amyloid precursor protein (APP) intracellular domain (AICD) increase

Ca2+ release from stores

in Alzheimer’s disease explain phenotypic remodelling by what does the abnormal amyloid metabolism result in

upregulation of neuronal Ca2+ signalling to induce an initial decline in memory

what does the voltage sensitivity turn NMDA receptors into in phenotypic remodelling in alzheimers disease

coincidence detectors

• glycine site, zinc site, proton site

what does AICD increase in phenotypic remodelling in alzheimers disease

Ca2+ leak through RyR

what does AICD decrease in phenotypic remodelling in alzheimers disease

Ca2+ buffering via calbindin

what is the end result of phenotypic remodelling in alzheimers disease

an amyloid dependent up-regulation of Ca2+ signalling

how does the resting level of Ca2+ increase in phenotypic remodelling in alzheimers disease

100nM to 300-500nM

remodelling of Ca2+ signalling in alzheimers disease may switch the brain from a system of…

memory storage (LTP) to one of memory loss (LTD)

how does Ca2+ do phenotypic remodelling in alzheimers disease

compartmentalisation of Ca2+ entry

what is a potential therapy for reversing Ca2+ dependent neurodegeneration

upping intake of vitamin D

how can positive feedback be critical for the onset and progression of alzheimers disease

• there is a bidirectional relationship between Ca2+ signalling and the amyloidogenic pathway

• while the amyloids stimulate and increase in Ca2+, Ca2+ signalling can stimulate the metabolism of APP

• the two way interaction produces an element of positive feedback

what does the positive feedback of AD make hard to determine

the primary cause of AD

what is the bidirectional relationship in AD between

Ca2+ signalling and the amyloidogenic pathway

what do amyloids stimulate an increase in, during AD

Ca2+

what can Ca2+ signalling stimulate in AD

the metabolism of APP

AD

alzheimers disease

describe Brody disease as an example of genotypic remodelling

• skeletal muscle genetic disorder characterised by stiffness and cramp brought on by prolonged Ca2+ elevation and a slowing of relaxation

• defect results from mutation in SERCA1 pump

• SR unable to refill with Ca2+

  • cytosolic Ca2+ remains elevated to relaxation is impeded

what is Brody disease also known as

Brody myopathy

give examples of Ca2+ signal remodelling in cancerous cells

• altered SERCA pump activity

• altered Ca2+ release through IP3 receptors

• altered resting level of Ca2+

whether Ca2+ signal remodelling helps to cause cancer or whether it is a consequence of cancer is…

unknown

why is whether Ca2+ signal remodelling helps to cause cancer or whether it is a consequence of cancer unknown?

there is a bidirectional relationship between Ca2+ signalling and cancer

explain the bidirectional relationship between Ca2+ signalling and cancer

• remodelling of Ca2+ signals causes changes in cellular activity

• changes in cellular activity cause remodelling of Ca2+ signals

what is APP

amyloid precursor protein

what is AICD

amyloid precursor protein intracellular domain