Question

1. Describe a possible signal transduction process invollving three second messengers.

2. Identify and explain the function of three key biochemical substances involved in regulating mitosis at the signal transduction level.

Answer 1

Hormones Acting through PIP2 Cascade-

The major player in this type of signal transduction is phospholipase C that hydrolyses phosphatidyl inositol in membrane lipids to 1,4,5-Inositol triphosphate (IP3) and Diacyl Glycerol (DAG) that act as second messengers. PIP3 (Phosphatidyl Inositol 3,4,5- phosphate) is another second messenger produced by the action of a phosphoinositide kinase. The phospholipase C may be activated either by G-proteins or calcium ions. DAG can also be generated by the action of phospholipase D that produces phosphatidic acid which is hydrolyzed to DAG. The binding of hormones like serotonin to cell surface receptor triggers the activation of the enzyme phospholipase-C which hydrolyzes the phosphatidyl inositol to diacylglycerol. IP3 can release Ca++ from intracellular stores, such as from endoplasmic reticulum and from sarcoplasmic reticulum. The elevated intracellular calcium then triggers processes like smooth muscle contraction, glycogen breakdown and exocytosis. PIP3 can be formed by the action of PI3-kinases that are activated through growth factors and cytokine mediated receptor tyrosine kinases. PIP3 which is a lipid secondmessenger has a role in regulation of cell motility, membrane trafficking and cell survival signaling pathways. The major mediator of PIP3 action is PKB (Protein kinase B) which has a role in glucose transport, glycogen metabolism and cell death signaling pathways. Active PKB/Akt is the major mediator of PIP3 action. It represses the activity of cell death signaling pathways. The PDK (Phosphatidyl inositol dependent kinase) and IP3 kinase are also involved in glucose transport and glycogen metabolism. There is “cross talk” between the various signal transduction pathways that are coordinately regulated.

Diacylglycerol Pathway -
Diacylglycerol (DAG), the messenger formed by the hydrolysis of PIP2 activates protein kinase C (PKC) which in turn would phosphorylate other target proteins. PKC activates several serine threonine kinases that phosphorylate several substrates including transcription factors, ion channels and transporters. Most effects of IP3 and DAG are found to be synergistic. DAG also increases the affinity of protein kinase-C for calcium. The enzymes are thus activated, even at physiological levels of calcium within the cell.

So, the three second messengers are - IP3, Calcium and DAG. All these gets involved in signalling via G-protein coupled receptors.