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MEDICAL BIO > WEEK 9 - Calcium function and homeostatsis: calcium channels > Flashcards

WEEK 9 - Calcium function and homeostatsis: calcium channels Flashcards

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1
Q

A rise in pre-synaptic calcium triggers….

A

synaptic vesicle fusion

converting an electrical signal into a chemical signal for neurotransmission

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2
Q

neuronal functions of Ca2+
types of vesicles

A

small synaptic vesicles
- (neurotransmitters e.g. glu)
- released with (steep) rise in Ca2+ to 100-200uM at channels

larger dense core vesicles (LDCV):
- neuropeptides, amines
- higher affinity for Ca2+ (0.4uM)
- little Ca2+ reach LDCVs away from active zones
- release with a delay of 50ms
- require high-frequency stimulation, which causes a higher rise in Ca2+

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3
Q

neuronal functions of Ca2+
Releasable pool:

A

vesicles at active zone, released at low firing frequencies

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4
Q

neuronal functions of Ca2+
reserve pool

A

tethered to cytoskeleton, mobilised by repetitive stimulation
required Ca2+ dependent phosphorylation of synapsin

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5
Q

neuronal functions of Ca2+
phases of vesicle release all require

A

Ca2+

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6
Q

neuronal functions of Ca2+
phases of vesicle release

A
  1. docking: SNARE complex at active zones, Syntaxin associated with VGCCs
  2. priming: soluble proteins form a complex with SNARE: partial fusion of vesicle and pre-synaptic membrane
  3. exocytosis: opening of fusion pore: Synaptotagmin is the Ca2+ sensor, binds Ca2+ changes conformation allowing fusion
  4. endocytosis and vesicle recycling: dynamin-GTP triggers fission of vesicle after invagination; GTP state requires Ca2+
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7
Q

neuronal functions of Ca2+
multiple types of Ca2+ transient signals can..

A

transmit vast amounts of information at different timescales

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8
Q

neuronal functions of Ca2+
calcium-regulated processes in neurons

A

neurotransmission (<1ms)

channel activity (>1ms)

short term plasticity (>100ms)

long term potentiation (up to 10s of secs)

long term depression (10s of secs to min)

gene expression (10s of mins)

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9
Q

intracellular Ca2+ levels rise in neurons through various mechanisms:
concentration gradient is the…

A

driving force:

extracellular Ca2+ levels (1mM) are 10,000 higher than intracellularly (100nM at axonal terminal)

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10
Q

intracellular Ca2+ levels rise in neurons through various mechanisms:
from extracellular space PM calcium channels:

A
  • voltage-gated calcium channel (VGCC)
  • ligand operated e.g. NMDAR
  • ORAI: activated when ER storing Ca2+ levels are depleted
  • TRP
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11
Q

intracellular Ca2+ levels rise in neurons through various mechanisms:
ER calcium channels

A

Via IP3R from
- IP3 production from PLCBeta and G-proteins
- IP3 production from PLCGamma and tyrosine phosphorylation

Via RyR
- Ca2+ induced Ca2+ release

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12
Q

Voltage-Gated calcium channels (VGCC)

A

VGCC are specific for Ca2+

multiple types of VGCC with different activation voltage, conductance and time course of inactivation

alpha1 subunit forms the channel, other subunits are accessory

many types of alpha1 subunit: made by 6 genes each alternatively spliced

(Wide range of different gates
- Different location
- Different voltage requirement
- Etc.)

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13
Q

Voltage-Gated calcium channels (VGCC)
L-type Ca2+ channels

A

dendrites (post-synaptic)

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14
Q

Voltage-Gated calcium channels (VGCC)
N-, P- and Q- type Ca2+ channels

A

neurotransmitter release (pre-synaptic)

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15
Q

Voltage-Gated calcium channels (VGCC)
T-type Ca2+ channels

A

thalamis

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16
Q

Distinct distribution of VGCCs in neurons and their functions

A

Different voltage gated channels in different locations in the neuron

L: dendrites, soma gene expression

P/Q: pre-synaptic neurotransmitter release

T: dendrites, oscillations

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17
Q

ligand operated calcium channels: Glu receptors
types

A

IONOTROPIC
- AMPAR –> action potential, cations: Na+, K+, Ca2+
- NMDAR –> coincident detector: Ca2+

METABOTROPIC
-Ca2+
- cAMP
longer slower effects, second messengers
Not operated by voltage
Operated by the presence of glutamate

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18
Q

multiples types of calcium channels in neurons

A

Glu receptors
- AMPA
- NMDAR

SOC: store-operated Ca2+ channels:
ORAI: links PM with ER via STIM1

ARC

TRP

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19
Q

multiples types of calcium channels in neurons
other Ca2+ channels

A

Gial cells
- Have as many gial cells as neurons just dontknow as much about them
- Larger than neurons
- ATP neurotransmitter

  1. niocontinic acetylcholine receptors
  2. ATP activates P2XR ionotropic and P2YR metabotropic receptors in glia (astrocytes) inducing Ca2+ waves in astrocytic networks

P2XRs causes rapid signaling and P2YR a long term effect including gene expressioon

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20
Q

distribution of calcium channels in neurons

A

into the cell cytosol:
- VOCC (electrical signal), AMPAR and NMDAR (neurotransmitter) from outside
- IP3R, RyR from ER

ORAI into ER

Extrusion of Ca2+ out of the cell cytosol:
- PMCA: plasma membreane Ca2+ ATPase
- NCX: plasma membrane Na+/Ca2+ exchanger
- SERCA: moves Ca2+ back into ER
- MUC: same as SERCA but in mitochondria

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21
Q

why are different types of Ca2+ channels distributed in different locations in neurons

A

Because have different structures for locations
Localised control of calcium
(specific channel, specific properties, precise location)
Very regulated events

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22
Q

different types of Ca2+ channels and their location

A

dendritic spine (post synaptic):
NMDAR, L-TYPE, RyR, IP3R

pre-synaptic:
P/Q TYPE

Dendrite:
AMPAR

Soma:
L-TYPE

ER:
RyR

23
Q

what do Ca2+ microdomains enable

A

Ca2+ microdomains enable it to carry out multiple functions within one neuron and with synaptic specificity

24
Q

microdomains

A

sites where Ca enters the cytoplasm either from the surface or from internal stores

25
Q

Ca2+ microdomains
Ca2+ plumes receives different names depending on..

A

the site and channel type of origin

Ca2+ pulsles, oscillation

encodes a tremendous amount of information

microdomains enable Ca2+ to have multiple functions in each neuron

synaptic specificity

Glial cells also communicate through Ca2+

26
Q

Ca2+ microdomains keep high levels of Ca2+..

A

very localised

enabling multiple very specific functions
e.g. synapses

27
Q

Ca2+ microdomains keeping Ca2+ localised:
Ca2+ is segregated spatially into microdomains by…

A

diffusion barriers and Ca2+ buffers (Prevent calcium from diffusing away)

restricting Ca2+ to within 50nm of the channel mouth

28
Q

Ca2+ microdomains keeping Ca2+ localised:
Ca2+ concentration rises to…

A

100-200uM within 10nm of channel mouth for vesicle release

29
Q

Ca2+ microdomains keeping Ca2+ localised:
Ca2+ functions..

A

locally

vesicle release, modulation of Ca2+ channels

30
Q

Ca2+ microdomains keeping Ca2+ localised:
diffusion of Ca2+ is…

A

buffered by many Ca2+ binding proteins

31
Q

Ca2+ microdomains keeping Ca2+ localised:
how does concentration drop

A

concentration drops quickly from 100 to 1uM

Ca2+ diffuses 0.1-0.5uM

32
Q

Ca2+ microdomains keeping Ca2+ localised:
how long before Ca2+ is bound

A

lasts 30ms before Ca2+ is bound

33
Q

Ca2+ binding proteins:
buffering

A

many soluble proteins bind Ca2+ to maintain its background cytosolic concentration low

  • parvalbumin (cytosolic)
  • calbindin (cytosolic)
  • calretquilin (ER)

Keeps free calcium levels low
Allowing for the spikes to be specific

34
Q

Ca2+ binding proteins:
Ca2+ sensors

A

Synaptotagmin: vesicle release

Calmodulin:
EF-hand motif. calcium binding induces a conformational change
mediator of most Ca2+ second messenger functions:
- exocytosis
- activation of kinases e.g. CaMKII
- metabolism
- gene expression
- DNA replication
- migration
- cell proliferation

35
Q

Ca2+ extrusion keeps cytosolic Ca2+ levels low

A

plasma membrane Ca2+ ATPase (PMCA):
- moves cytosolic Ca2+ outside the cell

sarcoplasmic Ca2+ ATPase (SERCA):
- moves cytosolic Ca2+ into ER intracellular stores

MUC: transfers Ca2+ into mitochondria

36
Q

Neuronal functions of Ca2+

A
  1. electrical signal: contribution to action potential
  2. second messenger
37
Q

second messenger function of Ca2+

A

Direct binding of calcium binding proteins, channels and enzymes:
- Annexins, channels, PKC, calpain

Binding to calmodulin to then regulate channels, other proteins and gene expression:
- NMDAR
- CaMKinase
- Calcineurin
- Calcium-ATPase
- PDE
- Adenylate-cyclase

gene expression via transcription factor CREB

38
Q

functions of Ca2+ as a second messenger:
Neuro-transmission

A

synaptic vesicle release

39
Q

functions of Ca2+ as a second messenger:
regulation of channels

A

modulation neuronal excitability

40
Q

functions of Ca2+ as a second messenger:
exocytosis

A

secretion of various molecules

41
Q

functions of Ca2+ as a second messenger:
regulation of

A

synaptic plasticity
learning and long-term memory

involving NMDAR, CaMKII

42
Q

functions of Ca2+ as a second messenger:
long term…

A

potentiation and depression

LTP and LTD

43
Q

functions of Ca2+ as a second messenger:
gene expression

A

CREB

44
Q

functions of Ca2+ as a second messenger:
motility

A

involving the cytoskeleton

45
Q

functions of Ca2+ as a second messenger:
regulation of

A

cell survival and cell death (apoptosis)

high levels cause cell death

46
Q

functions of Ca2+ as a second messenger:
autoregulation

A

Ca2+ homeostasis is regulated by Ca2+ itself, transcriptionally and post-transcriptionally

47
Q

dysregulation of Ca2+ levels in neurons results in…

A

various pathologies

dysregulation of Ca2+ homeostasis leading to high Ca2+ concentrations causes cell death (excitotoxicity) and is associated with multiple brain diseases

ALS: amyotropic laterial sclerosis
HD: huntington disease
Ataxia
AD
PD
migrane

48
Q

summary neuronal calcium functions and homeostasis:
Ca2+ can have two types of function in neurons:

A

electrical signal and function as a second messenger

49
Q

summary neuronal calcium functions and homeostasis:
oscillations and transients in Ca2+ levels encode…

A

information on synaptic strength and drive a wide variety of cellular process

50
Q

summary neuronal calcium functions and homeostasis:
multiple types of calcium channels enable…

A

extracellular Ca2+ to get into the cell cytosol and pumps extrude Ca2+ back outside the cell or take it into the ER stores

51
Q

summary neuronal calcium functions and homeostasis:
the concentration of Ca2+ is spatially restricted into…

A

microdomains

by Ca2+ binding proteins that keep background Ca2+ levels low (buffereing)

52
Q

summary neuronal calcium functions and homeostasis:
microdomains enable Ca2+ to have…

A

multiple, highly specific functions at once in the same neurons

e.g. in different synapses

53
Q

summary neuronal calcium functions and homeostasis:
the most abundant Ca2+ binding protein is

A

calmodulin, and together drive the functions of Ca2+ as a second messenger

MEDICAL BIO (12 decks)

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