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Block Two Cell Signaling > Calcium Signaling > Flashcards

Calcium Signaling Flashcards

1
Q

Ca2+ gradient

A

STEEP gradient across cell membrane; 20,000 fold lower in cytoplasm than in extracellular fluid; plus cells have membrane potential of -60mV favoring Ca2+ influx increasing gradient further; PM VERY impermeable for Ca2+

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2
Q

Ca2+ cell signals

A 
non excitable cells
-fertalization
- proliferation
- metabolism
- secretion
excitable cells 
- neurons
- B cells
- skeletal muscle
- cardiac muscle
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3
Q

Ca2+ On reactions

A
  • no spontaneous transport across cell; can be voltage or ligand gated channel
  • GPCR and enzyme linked receptors -> activators/ agonists -> bind with Ca2+ channel -> Ca2+ released from intracellular stores in SR/ER to cytoplasm
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4
Q

Ca2+ Off reactions

A
  1. Ca2+ pump: SR, ER, PM; use ATP to pump Ca2+ against [ ] gradient
  2. Na+/ Ca2+ ; use Na+ gradient to move Ca2+ across cell membrane
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5
Q

Ca2+ enters cytoplasm

A

small amount binds to calcium effector proteins rest is bound to buffers in cytoplasm or pumped into SR or ER via SERCA pump; in stores bound to calcium-binding proteins (calsequestrin in SR) allowing lg amounts of calcium accumulation; if high [Ca2+] mitochondria will accumulate calcium

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6
Q

Name of calcium binding protein for SR

A

calsequestrin

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7
Q

SERCA stands for

A

sarco(end)plasmic reticulum Ca2+-ATPase

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8
Q

SR

A

ER in muscle cells

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9
Q

intracellular Ca2+ stores

A

SR, ER, mitochondria

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10
Q

Ca2+ extrusion

A

Removing Ca2+ from cell
Ca2+ in plasma membrane (Ca2+-ATPase) in all cells
Na+/Ca2+ exchanger (NCX) in excitable cells; couples Ca2+ to Na+ moving down electrochemical gradient

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11
Q

Ca2+ signal ranges

A

depends on cell type; depends on combination of on and off reactions and effectors; Amplitude, Duration, Oscillation Frequency, Spatial

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12
Q

Amplitude

A

Ca2+ signals can be v large (nerve cells) or v small (non-excitable cells)

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13
Q

duration

A

brief (microseconds) (nerve cells) or persist (hours) (transcription and cell proliferation)

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14
Q

oscillation frequency

A

oscillate (or spike) in cell types, duration of spike and their frequency determine strength and nature of response; responses can be oscillatory but Ca2+ oscillations may elicit a sustained response

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15
Q

spatial

A

may be throughout whole cell or in small region of cell

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16
Q

global Ca2+ wave intacellular

A

signal spreads throughout cell b/c coordinate activity numerous elementary events-> signal spreading throughout cell ex muscle contraction and gene transcription

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17
Q

global Ca2+ wave intercellular

A

signal spreads to neighboring cell; ex wound healing and insulin secretion from pancreatic islets

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18
Q

Elementary events

A

localized within cell (Ca2+ enters cytosol from external store)
ex. vesicle secretion, opening Ca2+-activated channels, and mitochondria metabolism

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19
Q

Ca2+ activates Ca2+ effectors

A 
Ca2+ binding protein
Ca2+/ calmodulin related enzyme
Ca2+ regulated enzyme
Ca2+ responsive transcription factor
Ca2+ sensitive ion channel
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20
Q

Ca2+ signaling in excitable cells

A
  • usually initiated by voltage-sensitive calcium channels in PM = activated by cell depolarization (some also have ligand-gated or receptor-operated channels which open bc binding of extracellular transmitter)
21
Q

Nerve terminal

A

exocytic release of synaptic vesicles activated by influx Ca2+ through voltage-sensitive calcium channel; channel bound to syntax, SNAP-25, and synaptobrevin which carry out fusion event initiated by synaptotagmin

22
Q

Cardiac muscle cell

A

depolarized; l-type voltage sensitive calcium channels in T tubule membrane activated -> Ca2+ in cell -> ryanodine receptors activated -> SR release Ca2+ -> amplified signal -> Ca2+ binding to troponin C -> myofibril contraction

23
Q

ryanodine receptor

A

intracellular Ca2+ release channel

24
Q

mitochondria Ca2+

A

Ca2+ influx into mitochondria stimulates mitochondrial metabolism to provide ATP necessary to sustain contraction

25
Q

phospholamban

A

inhibitor of SERCA pump, inactivated by cyclic AMP-dependent phosphorylation -> Ca2+ -> SR

26
Q

Ca2+ signaling in non-excitable cells

A

involves receptor activation and generation of second messengers that ultimately -> increase in intracellular Ca2+ via several mechanisms
-Inositol Phospholipid Signaling

27
Q

Inositol Phospholipid Signalling

A

GPCR and TK linked receptors stimulated -> activation phospholipase C (PLC) -> cleave phosphatidyl inositol 4,5-bisphosphate (PIP2) from diacylglycerol and inositol triphosphate (IP3)
->diacylgycerol recruits protein kinase C (PKC) to PM -> activates PKC
and
-> IP3 binds IP3 gated Ca2+ release channels (IP3 receptors) -> release Ca2+
overall
-> increase cytoplasmic Ca2+

28
Q

protein kinase C

A

feedback loop for Ca2+; diacylgylcerol provides landing site for this

29
Q

IP3

A

inositol triphosphate; MAJOR signaling hub modulating this can -> bispectrum of signals

30
Q

How do non excitable cells maintain Ca2+ signals for prolonged time

A

activate calcium channels in PM allowing Ca2+ influx into cells; most common channels= store-operated calcium channels (SOCs)

31
Q

Store operated calcium channels (SOCs)

A

IP3 -> intracellular calcium stores empty -> activation store-operated calcium channels
include CRAC channel

32
Q

Orali

A

Orai1 form CRAC channel pore

33
Q

CRAC channel opening

A

Depletion Ca2+ stores leads to activation and accumulation of STIM1 in regions ER close to PM; Orali accumulates in apposed regions PM; molecular interaction these 2 proteins -> Ca2+ channel opening

34
Q

STIM1

A

ER Ca2+ sensor; unusual bc inhibited by Ca2+ so when Ca2+ levels in cytoplasm high this is inhibited which in turn stops it from activating CRAC channel preventing Ca2+ release

35
Q

Restoration resting Ca2+ levels

A

receptor stops signaling -> no more IP3 produced -> IP3 channels close -> Ca2+ pumped back into stores by SERCA -> stores refill -> termination signal for PM calcium channel activation
At same time Ca2+ pumped out cell via PM Ca2+-ATPase (PMCA) pump

36
Q

How does calcium exert its effect

A 
binding to calcium effector proteins
Ca2+ binds to 
- calcium binding proteins
- calmodulin-sensitive kinases
-  Ca2+/ calmodulin-regulated enzymes
- Calcium sensitive transcription factors
- Calcium-sensitive ion channels
37
Q

Calcium binding proteins

A

Activated when bind calcium and interact with other proteins; include calmodulin (euk cells), troponin C (skeletal and cardiac muscle), synatotagmin (synaptic vesicles)

38
Q

Calmodulin-Sensitive kinases

A

multifunctional calmodulin-dependent protein kinases (CaM-kinases), smooth muscle myosin light chain kinase

39
Q

Ca2+/ calmodulin-regulated enzymes

A

PM Ca2+-ATPase, calcineurin (calcium-senstive phosphatase)

40
Q

Calcium sensitive ion channels

A
  • Ca2+ activated K+ channels

- Ca2+ activated chloride channels

41
Q

Calmodulin

A

dumbbell shaped protein 2 globular ends connected by alpha helix; each end 2 Ca2+ biding domains, those in carboxyl-terminal part have tenfold higher affinity for Ca2+

42
Q

Ca2+/ Calmodulin complex

A

when binds to target protein undergoes conf change wraps around region target protein and activates it

43
Q

CaM kinase II

A

Ca2+/ Calmodulin- Dependent Protein Kinase II; multifunctional protein kinase; acts as frequency detector, can decode oscillatory Ca2+ signals; molecular memory device (remains active under certain conditions even after Ca2+ signal terminated); contains 12 homologous subunits

44
Q

Molecular memory

A

inactive CaM-kinase subunit binds Ca2+/ Calmodulin its conformation changes -> exposure catalytic domain enzyme -> phosphorylation inhibitory domain neighboring subunit

45
Q

Autophosphorylation CaM-kinase

A

prolongs enzyme activity two ways

  1. Traps bound Ca2+/ calmodulin so doesn’t dissociate from enzyme until Ca2+ returns to resting levels for 10 sec min
  2. Coverts enzyme to Ca2+ independent form so remains partially active after Ca2+/Calmodulin dissociates from it; activity remains until autophosphorylation enzyme overwhelmed by protein phosphatase activity
46
Q

CaM-kinase II low frequency Ca2+ spikes

A

CaM-kinase II inactivates after each spike bc completely dephosphorylated before next Ca2+ spike arrives

47
Q

CaM-kinase II spike frequency increase

A

spike frequency increases more subunits (12 subunits total) of enzyme stay phosphorylated between spieks

48
Q

CaM-kinase II spike frequency V high

A

spike frequency high enough enzyme autophosphrylatd on all subunits and maximally active; once enough subunits phosphorylated enzyme can be maintained in highly activated state with low frequency Ca2+ spikes

Block Two Cell Signaling (12 decks)

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