M&R 5.2 - Control of Cytosolic Ca2+ Flashcards
What are the extracellular and intracellular concentrations of Ca2+ at rest?
- Extracellular = 1-2mM
- Intracellular = ~100nM
= A large inwards gradient
What are the advantages of a large inwards gradient of Ca2+?
- Can have a rapid change with little Ca2+
- Not a lot needs to be removed to return to basal states
What are the disadvantages of a large inwards gradient of Ca2+?
- Requires a lot of energy
- Leads to cell death due to overload if it can’t be dealt with
How does the membrane contribute to the control of intracellular Ca2+?
- Relatively impermeable
- Ca2+ can only move through specific ion channels when open
What is the function of NCX?
- Movement of 3Na+ in: 1Ca2+ out (electrogenic antiporter) - Causes a slight depolarisation due to net movement of +1 in
- Low affinity, high capacity
- Uses gradient set up by Na+ pump
How does Ca2+ATPase work?
- Moves Ca2+ across the membrane against its concentration gradient using ATP hydrolysis
- Ca2+ binds to Calmodulin first
- High affinity, low capacity = removes residual Ca2+
What is a Ca2+ buffer?
- Diffusion limiters
- ATP
- Ca2+ binding proteins e.g. Calbindin
- Trigger proteins
What happens when Ca2+ binds to trigger proteins?
- Produces a conformational change
- Alters function e.g. Calmodulin, Troponin
What is the function of Ca2+ buffers?
- Ensures that Ca2+ doesn’t move very far in the cell before binding to something
- Distance moved is proportional to concentration of binding molecules and their saturation
Describe how selectively altering membrane permeability raises intracellular Ca2+ levels?
- VOCC channels open due to a conformational change after depolarisation
- Ca2+ moves into the cell down its gradient
What is the significance of having multiple types of Ca2+ channel?
- Different types have different properties
- Ensures the system is flexible
Give two examples of Ionotropic receptors
- NMDA/AMPA Receptors for Glutamate
- Nicotinic Acetylcholine Receptors
How do ionotropic receptors raise intracellular Ca2+ levels?
- Ligand binds to the channel causing a conformational change
- If selective to Ca2+, Ca2+ moves in down chemical (and maybe electrical) gradient
What is the significance of the endoplasmic/sarcoplasmic reticulum in raising calcium levels?
- Rapidly releasable Ca2+ store using SERCA
- Having binding proteins inside = can hold more Ca2+ than if it was just packed therefore increasing its capacity
How is Ca2+ release from SER controlled?
- GPCR
- CICR
Describe the GPCR mechanism for Ca2+ release from the SER
- Agonist binds to GPCR = activated
- Alpha-Q subunit dissociates and stimulates Phospholipase C
- Phospholipase C cleaves PIP2 to form IP3 and DAG
- IP3 binds to lgCa2+ channels on SER membrane allowing a Ca2+ influx into cell down its gradient
Describe the mechanism for calcium induced calcium release (CICR)
- Ryanodine receptors are activated by Ca2+ (due to increase in intracellular levels)
- Open due to a conformational change
- Influx from stores into cardiac myocyte = excitation contraction coupling
Describe the location of Ryanodine receptors and the significance of this
- Next to VOCC on t-tubules
- Rapid transmission of depolarisation
- Rapid release NEXT TO contractile machinery
How does Na+ contribute to Ca2+ influx?
- Increase of Na+ concentration in microdomains next to plasma domains
- Reverses NCX = small Ca2+ influx
How is [Ca2+]in returned to normal?
- Inactivation of Na+ = less depolarised
- Causes Ca2+ channels to close and decreases [Na+]in
- NCX returns to normal direction so moves Ca2+ out of cell normally
What happens if [Ca2+]in doesn’t return to basal levels?
- Activates potent enzymes within the cell
- Causes cell death due to hypoxic injury
How are Ca2+ stores refilled?
- Recycled in cardiac myocytes
- VOCC/Capacitative Ca2+ entry = store empties so signal is sent to store operated channel = influx
What is the significance of capacitative entry?
Regulation of physiological processes e.g. secretion
What happens if the stores aren’t refilled?
- Decreases contraction
- Demand of CICR can’t be met
