Calcium Signaling

Question 1

Fx. of cytoplasmic Ca buffers?

Answer 1

Cytoplasmic Ca2+ buffers are proteins that bind to free Ca2+ in the cell. buffers restrict the spatial spread of free Ca2+ in order to localize calcium/ control signaling pathways .
Buffers also store Ca2+ until it can be properly transported. After calcium ions are released from their effectors, buffers sequester them until they are transported out of the cell, which is a relatively slow process

Question 2

How does extracellular ER move out of the SR/ER into the cytoplasm?

Answer 2

Calcium ions are released from the ER/SR into the cytoplasm through Ca channels
mediated by ryanodine and inositol triphosphated (IP3) receptors.
Recognition of Ca2+ in the
cytoplasm by ryanodine receptors triggers the release of Ca2+ from the ER/SR.
This is a positive
feedback mechanism: the release of calcium ions is sensed by the receptors, leading to further calcium release. IP3 receptors respond to IP3 (a secondary messenger in a G-coupled protein receptor signaling pathway) to activate Ca2+ channels and stimulate Ca2+ influx into the cytoplasm from the ER/SR.

Question 3

How does calcium get extracellular and into ER?

Answer 3

Ca put out of cytoplasm into the extracellular space/lumen of the ER/SR by Ca2+ pumps that hydrolyze ATP. pump is the Plasma Membrane Ca2+ATPase (PMCa ATPase) in the cell membrane and it is Sarco/Endoplamic Reticulum Ca2+ ATPase in the ER/SR (SERCa ATPase).
Ca can also be put into the extracellular by Na+/Ca2+ exchangers.

Question 4

EF hands domains and C2 domains?

Answer 4

EF hands and C2 domains are both structural motifs that depend on coordination with Ca.
EF hands are helix-loop-helix domains with two perpendicular alpha helices connected by a short loop that coordinates with Ca. Calmodulin is a protein made up of four EF hands.
C2 domains are structural domains on proteins that target the protein to the cell membrane. PKA has a C2 domain. The C2 domain coordinates with 2 or 3 Ca ions, causes C2 to bind to PS in PM.
Other Ca effectors have EF-hand domains and many other proteins that bind with PM contain C2 domains (such as synaptotagmin ,which is involved in NT release).

Question 5

Ca conc higher where?

Answer 5

Higher by a lot extracellularly.

Ca is not synthesized for signaling! so this is why it’s so fast.

Question 6

Sources of Ca?

Answer 6

Ion Channels
Plasma membrane: Voltage- and ligand-gated Ca2+ channels, store-operated Ca channels (Orai1)… operate when a store like ER is depleted. Ca moves from outside cell into cytoplasm
ER/SR, (nuclear envelope): IP3 receptors, ryanodine receptors. Ca from lumen of ER/SR to cytoplasm.
Mitochondria Mitochondrial uniporter, permeability transition pore (MPTP). Direction depends on Ca2+ gradient. MPTP contributes to cell death during stroke and myocardial infarction.

Question 7

Sinks of Ca?

Answer 7

Transporters (active, against electrochemical gradient). Movements much slower than ion channels

Ca pumps use ATP to move Ca out of cytoplasm into extracellular space (PMCA pumps) or into lumen of ER/SR (SERCA pumps)

Na/Ca exchangers (NCX, RetX) extrude Ca out across PM or from mitochondria into cytoplasm. NCX exchanges 3Na:1Ca, deriving energy from Na+ gradient. Net entry of 1 positive.

Question 8

Calmodulin

Answer 8

HIGHLY conserved. Has 4 EF hand Ca binding sites, when bound it changes conformation and can go one to affect other things.
Transduces ca signals.