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Flashcards in Calcium Signaling Deck (17)

1. Describe the functions of cytoplasmic Ca2+ ion buffers and how these buffers affect cytoplasmic Ca2+ signals.

2. Describe the routes by which extracellular Ca2+ enters the cytoplasm, the routes by which Ca2+ moves out of the ER/SR into the cytoplasm, and the routes by which Ca2+ is extruded from the cytoplasm (a) into the extracellular space and (b) into the lumen of the ER/SR.

3. Describe EF hands and C2 domains, identify the archetypical protein that contains EF hands and the archetypical protein that contains a C2 domain, and determine whether these domains are present in other proteins.



Parvalbumin is a cytoplasmic buffer. Knowing that, what does it likely do?

The cytoplasmic buffers (e.g., parvalbumin) tend to restrict the spatial and temporal spread of Ca2+. The buffers also serve as a temporary storage site for Ca2+ while the relatively slow transport processes are operating.


Calsequestrin is an ER/SR Ca buffer. Knowing that, what does it likely do?

In the ER/SR lumen, high-capacity low affinity buffers (e.g., calsequestrin) allow large quantities of Ca2+ to be stored without the generation of a large gradient in the concentration of free Ca2+.

[From lecture notes: calsequestrin has a high capacity but low affinity for Ca]


Unlike other signals which are generated by catalytic enzymes, Ca2+ enters the cytoplasm (resting ca 50-100 nM) from “sources” where it can be ~2 mM. So what?

Thus, onset of Ca2+ signals is far more rapid than that of other signals.


How does Ca enter the cytoplasm (from what 4 structures?)

Mitochondria, ECF, ER/SR, [Nuclear membrane - mentioned only in lecture]


By what method does Ca enter the cytoplasm from the ECF?

Voltage gated Ca2+ channels
Ligand gated Ca2+ channels
store-operated Ca2+ channels (Orai1)

[store operated channels sense depletion of Ca in the ER and open accordingly]


By what methods does Ca enter the cytoplasm from the ER/SR?

IP3 receptors
Ryanodine receptors


By what methods does Ca enter the cytoplasm from the mitochondria?

Mitochondrial uniporter, permeability transition pore (MPTP). Direction depends on Ca2+ gradient. MPTP contributes to cell death during stroke and myocardial infarction.


How does Ca enter the cytoplasm from the ER?

Calcium ions are released from the ER/SR into the cytoplasm through calcium 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.


How is calcium moved from the cytoplasm into the ECF?

Calcium ions are extruded from the cytoplasm into the extracellular space or the lumen of the ER/SR by Ca2+ pumps that hydrolyze ATP. This pump is called the Plasma Membrane Ca2+ ATPase (PMCa ATPase) in the cell membrane and it is called the Sarco/Endoplamic Reticulum Ca2+ ATPase in the ER/SR (SERCa ATPase). Calcium ions can also be extruded into the extracellular space by Na+/Ca2+ exchangers.


Is there an Na/Ca transporter in the pm? If so, how does it work?

Yes. 3Na in, 1 Ca out.


Is there an ATP driven Ca transporter in the pm? What is it called?

Yes. 1 ATP moves 1 Ca. PMCa ATPase


Is there an ATP driven Ca transporter in the ER? What is it called? Which way does it go?

SERCa ATPase moves 1Ca into ER for 1ATP.


What is Calmodulin?

Calmodulin is an intracellular calcium receptor found ubiquitously in eukaryotes. It is capable of regulating biological activities of many cellular proteins and transmembrane ion transporters mainly in a Ca2+-dependent manner. When the intracellular calcium level rises to 10-5 M, four Ca2+ ions bind to calmodulin, and this Ca2+-calmodulin complex binds the target proteins, initiating various signalling cascades.

[It is also freakishly conserved, each person has 3 copies of the gene with NO polymorphisms]


What are EF hands? Which protein has them that we talked about?

EF hands are helix-loop-helix domains with two perpendicular alpha helices connected by a short loop that coordinates with calcium ions. Calmodulin is a protein made up of four EF hands.


What is a C2 domain?

C2 domains are structural domains on proteins that target the protein to the cell membrane. Protein Kinase A has a C2 domain. The C2 domain coordinates with 2 or 3 calcium ions.


What other proteins contain EF hands?

parvalbumin (a cellular Ca2+ buffer)
calpain (a Ca2+-activated protease)