Describe the principles of cell signalling using the example of the control of blood glucose concentration by glucagon, limited to: • binding of hormone to cell surface receptor causing conformational change • activation of G-protein leading to stimulation of adenylyl cyclase • formation of the second messenger, cyclic AMP (cAMP) • activation of protein kinase A by cAMP leading to initiation of an enzyme cascade • amplification of the signal through the enzyme cascade as a result of activation of more and more enzymes by phosphorylation • cellular response in which the final enzyme in the pathway is activated, catalysing the breakdown of glycogen

Cell signaling is the process by which cells respond to external signals, such as hormones, to trigger specific cellular responses. A clear example is the regulation of blood glucose levels by glucagon, a hormone released when blood glucose is low. Here’s a step-by-step description of how glucagon signals target cells in the liver to break down glycogen and release glucose into the bloodstream:

1. Binding of Glucagon to Cell Surface Receptor

When blood glucose levels are low, the pancreas secretes glucagon into the bloodstream. Glucagon travels to target cells, such as liver cells (hepatocytes), and binds to a specific G-protein-coupled receptor (GPCR) on the cell membrane. This binding causes a conformational change (shape change) in the receptor, which is essential for activating the next steps in the signaling pathway.

2. Activation of G-Protein

The conformational change in the receptor activates an associated G-protein on the inside of the cell membrane. The G-protein consists of three subunits (alpha, beta, and gamma) and, in its inactive state, binds GDP (guanosine diphosphate). Upon receptor activation, the G-protein exchanges GDP for GTP (guanosine triphosphate), causing the alpha subunit to dissociate from the beta and gamma subunits. The activated alpha subunit then moves along the membrane to activate the next component in the signaling pathway: adenylyl cyclase.

3. Activation of Adenylyl Cyclase and Formation of cAMP

The activated G-protein alpha subunit binds to adenylyl cyclase, an enzyme embedded in the cell membrane. This interaction stimulates adenylyl cyclase to convert ATP (adenosine triphosphate) into cyclic AMP (cAMP), which acts as a second messenger inside the cell. The increase in cAMP levels is a critical step that relays the signal from glucagon at the cell surface to the interior of the cell, initiating a cascade of events.

4. Activation of Protein Kinase A by cAMP

cAMP binds to and activates protein kinase A (PKA), a key enzyme in the signaling pathway. In its inactive state, PKA consists of regulatory and catalytic subunits. When cAMP binds to the regulatory subunits, it causes them to release the active catalytic subunits of PKA. Activated PKA can now initiate an enzyme cascade that will ultimately lead to the breakdown of glycogen.

5. Signal Amplification through an Enzyme Cascade

Once activated, PKA phosphorylates and activates other enzymes in a sequence of steps, creating an enzyme cascade. This cascade significantly amplifies the signal because each activated enzyme can, in turn, activate multiple copies of the next enzyme in the pathway. For example, PKA phosphorylates and activates phosphorylase kinase, which then phosphorylates glycogen phosphorylase. Each step in this cascade activates more molecules, greatly increasing the effect of the initial glucagon signal.

6. Cellular Response – Glycogen Breakdown

The final enzyme in this cascade, glycogen phosphorylase, is now active and catalyzes the breakdown of glycogen into glucose-1-phosphate. This glucose-1-phosphate can then be converted into glucose-6-phosphate and, ultimately, free glucose, which is released into the bloodstream. This increase in glucose availability helps to restore blood glucose levels to normal.

Summary

This cell signaling pathway, initiated by glucagon, illustrates the principles of cell signaling, including hormone-receptor binding, G-protein activation, second messenger formation, enzyme activation and cascade amplification, and the cellular response. Each step ensures that even a small amount of glucagon can produce a large and rapid effect, effectively increasing blood glucose levels in response to the body’s needs.