1. Signal Transduction and Secondary Messengers Mahmoud Farhat

2. What is Signal Transduction? What are the Secondary Messengers involved in this process? How do they work?

3. Signal Transduction A basic process involving the conversion of a signal from outside the cell to a functional chemical change within the cell

4. Signal Transduction A ligand specifically and reversibly binds to a receptor forming a complex Once the ligand binds, secondary messengers are produced within the target cell

5. Signal Transduction General features of signal transduction that are common to all: 1. Signal interacts with a receptor 2. The activated receptor interacts with machinery producing a secondary signal 3. A change in the metabolic activity of the target cell occurs 4. Transduction event ends and the cell returns to prestimulus state

7. G Proteins G proteins bind GDP or GTP nucleotides They are made up of three different subunits associated with the inner surface of the plasma membrane and transmembrane receptors, which are called G protein-coupled receptors (GPCRs) Three subunits are: Gα – binds the nucleotides Gβdimer Gγ

8. G proteins In the inactive state, Gα has GDP in its binding site Ligand binds to GPCR causing a conformational change GDP leaves and GTP binds activating Gα and causing it to dissociate from the GβGγ dimer Activated Gα will then activate an effector molecule such as adenylyl cyclase – an enzyme that catalyzes the conversion of ATP to the secondary messenger cAMP

10. Secondary Messengers Main classes of secondary messengers: Cyclic nucleotides (cAMP and cGMP) Inositol trisphosphate (IP 3 ) Diacylglycerol (DAG) Calcium ions (Ca 2+ )

11. Cyclic Nucleotides Cyclic AMP (cAMP) Major secondary messenger used in many pathways of the body Adenylyl cyclase, activated by a G protein, synthesizes cAMP from ATP Some hormones that use cAMP: Glucagon LH Adrenaline

12. Cyclic Nucleotides Protein Kinase A is a type of protein that is activated by cAMP It is known as a cAMP-dependent protein kinase that phosphorylates target proteins to activate them

14. Cyclic Nucleotides Cyclic GMP (cGMP) Synthesized from GTP using guanylyl cyclase Effects of cGMP are mediated through Protein Kinase G – a cGMP-dependent kinase that phosphorylates target proteins cGMP serves as a secondary messenger for hormones such as ANP and nitric oxide

15. Inositol Trisphosphate and Diacylglycerol IP 3 and DAG are secondary messengers that are activated by G proteins Hormones like ADH, TSH, and angiotensin or NTs like GABA bind to GPCRs and activate an enzyme called phospholipase C (PLC)

16. PLC then hydrolyzes a specific phospholipid known as phosphatidylinositol-4,5- bisphosphate (PIP 2 ) Hydrolysis of this phospholipid yields two products: Diacylglycerol (DAG) Inositol-1,4,5-trisphosphate (IP 3 )

17. DAG recruits Protein Kinase C – a calcium dependent protein kinase that phosphorylates target proteins IP 3 makes calcium available for activation of PKC

18. Calcium (Ca 2+ ) Calcium is one of the most important and widely used secondary messenger throughout the body Muscle contraction Presynaptic neuron