Signal Transduction and Secondary

MessengersMahmoud Farhat

What is Signal Transduction?

What are the Secondary Messengers involved in this process?

How do they work?

Signal Transduction

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

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

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

G ProteinsG 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 nucleotidesGβ dimerGγ

G proteinsIn 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

Secondary Messengers

Main classes of secondary messengers:Cyclic nucleotides (cAMP and cGMP)Inositol trisphosphate (IP3)Diacylglycerol (DAG)Calcium ions (Ca2+)

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:GlucagonLHAdrenaline

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

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

Inositol Trisphosphate and Diacylglycerol

IP3 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)

PLC then hydrolyzes a specific phospholipid known as phosphatidylinositol-4,5-bisphosphate (PIP2)

Hydrolysis of this phospholipid yields two products:Diacylglycerol (DAG)Inositol-1,4,5-trisphosphate (IP3)

DAG recruits Protein Kinase C – a calcium dependent protein kinase that phosphorylates target proteins

IP3 makes calcium available for activation of PKC

Calcium (Ca2+)

Calcium is one of the most important and widely used secondary messenger throughout the body

Muscle contraction

Presynaptic neuron