Question

1. Calcium plays several roles in cells that are critical for second messenger signaling and overall cell function. Yet loss of calcium homeostasis can result in cell death.

a. List three cellular responses to a rise in cytosolic calcium

b. Calcium ionophores such as A23187 and Ionomycin can demonstrate that a loss of intracellular calcium can lead to cell death through necrosis. Explain this statement.

c. How is calcium important to the IP3/DAG pathway and why is this a two part event?

d. NMDA receptors are a type of glutamate receptor that is a non-selective ion channel. While we didn’t talk about this type of receptor in class you can learn more about this type of receptor via the internet. As a non-selective ion channel it passes most ions down its gradient. Why has there been a significant amount of research done to find NMDA blockers that can selectively block the influx of calcium into neurons in the event of stroke

Answer 1

a.

1. Increase in calcium can activate the ryanodine receptor to release enough calcium from the sarcoplasmic reticulum to initiate heart muscle contraction.

2. Rise in cytosolic calcium can activate Protein Kinase C which activates downstream signaling molecules.

3. In case of oocytes cytoplasm, rise in calcium levels due to calcium influx leads to activation of  NAD+ kinase and exocytosis of the cortical granules which causes a block to polyspermy.

b. A23187 is an ionophore which destroys the calcium gradient across cell. It acts as a channel which results in free flow of calcium into and out of the cell. In addition, it inhibits the ATP synthase of mitochondria. A23187 results in the high production of Reactive oxygen Species both intracellularly and extracellular which results in apoptotic signaling by the cell.

c.In case of IP3 - DAG pathway, Phospholipase C is activated by a receptor present on cell surface. It cleaves Phosphoinositol -4,5- bisphosphate to give rise to the Inositol Triphosphate. IP3 binds to the IP3 gate calcium channels present on Endoplasmic Reticulum. ER releases calcium ions which bind to their receptors present in Protein Kinase C. Protein Kinase C phosphorylates the downstream regulatory elements which regulate DNA expression.

d.

The NMDA receptor is a non-specific cation channel that results in Ca2+ and Na+ influx into the cell and K+ efflux out of the cell. When a pre synaptic neuron releases glutamate it binds to the NMDA receptor present on the post synaptic neuron. Binding of glutamate produces the the excitatory postsynaptic potential (EPSP) that increases the concentration of Ca2+ in the cell. Ca2+ essentially functions as a second messenger in several downstream signaling pathways. In cases of Alzheimer's diseases, there is an excessive production of glutamate which results is over activation of NMDA receptors. Thus there is a constant influx of calcium ions into the neurons which causes slow neuron death.