Ch 14 Signal Transduction Pathways

Signal transduction pathways

chain of events that convert molecular messages into a range of physiological responses

Transduction

the conversion of information of the presence or concentration of a signal molecule into other forms

Key Steps for Signal Transduction

• release of primary messenger (signal)

• reception of the primary message by a receptor, a membrane protein with an intracellular and extracellular component

• delivery of the message inside the cell by intracellular second messengers 

• activation of other molecules that directly alter the physiological response

• termination of the signal

Common secondary messengers 

• cAMP, cGMP

• Calcium ion

• Inositol 1,4,5-triphosphate (IP₃)

• Diacylglycerol (DAG) 

Seven-Transmembrane-Helix (7TM) Receptors

• large class of cell-surface receptors 

• transmit diverse information initiated by hormones, neurotransmitters, odorants, and light 

• nearly 1000 encoded in the human genome

• contain seven helices that span the membrane bilayer 

What does the binding of an agonist to the β-Adrenergic receptor result in?

stabilization of an activated conformation of the receptor

Agonists

ligands that activate receptors

What helices change the most upon agonist binding

5 and 6

What does ligand binding to 7TM receptors lead to?

the activation of heterotrimeric G Proteins

During the ligand binding to 7TM receptors that leads to the activation of heterotrimeric G proteins, the conformational change on the cytoplasmic side of the receptor activates a

G protein

When activated, what happens to the G protein?

Stimulates the activity of adenylate cyclase, an enzyme that catalyzes the conversion of ATP into cAMP 

The second messenger cAMP carries

the signal throughout the cell

During G protein activation, G protein exists as a heterotrimer consisting of alpha, beta, and gamma subunits. What are the roles of the subunits? 

• Alpha subunit (G_alpha) is bound to GDP

• Alpha and Gamma subunits anchored to membrane by covalently attached fatty acids 

G_alpha  

• interacts with surface of receptor, mostly helices 5 and 6 

• When bound to receptor, opens substantially enabling replacement of GDP with GTP 

How do activated G proteins transmit signals?

By binding to other proteins

Adenylate cyclase

• enzyme that converts ATP to cAMP

• Composed of 12 membrane-spanning helicies 

• catalytic part of 2 cycloplasmic domains 

In the beta-AP pathway, activated G_alpha binds

adenylate cyclase

• binding favors a more catalytically active conformation of the adenylate cyclase

• provides another level of amplification

Protein kinase A (PKA)

• protein that phosphorylates specific Thr and Ser residues in target proteins to alter their activity

• Consists of 2 regulatory (R) and 2 catalytic (C) chains (R₂C₂)

• Inactive in absence of cAMP 

• binding of cAMP to R chains frees the C chains which are catalytically activated when freed 

• Cyclic AMP stimulates the phosphorylation of many target proteins by activating protein kinase A 

How does epinephrine cause muscle contraction?

In cardiac muscles, PKA phosphorylates troponin I (apart of troponin complex that prevents myosin from binding to actin) 

• Phosphorylation weakens troponin binding to actin

• Actin can interact with myosin

What turns off G Protein?

After GTP hydrolysis and the release of Pi, the GDP-bound form of G_alpha reassociates with G_beta-gamma to re-form the inactive heterotrimeric protein 

What is the basic pathway for epinephrine signaling an alpha-adrenergic receptor?

• receptors that activate G_alphaq, a G protein that binds to and activates the enzyme phospholipase C when in its GTP form

• 1. Ca²⁺ ion to IP³ receptor

• 2. Ca²⁺ ion flows through protein kinase C

• 3. Phospholipase C cleaves and IP³ travels to IP³ receptor 

How does calcium activate calmodulin? What does calmodulin in turn target?

• Calmodulin binds calcium and activates some protein kinases

• Ca²⁺ binding to calmodulin induces substantial conformational changes in its EF hands 

  • Exposes hydrophobic surfaces that can bind proteins 

Protein phosphatases

enzymes required to hydrolyze phosphorylated proteins and return them to their initial states 

Protein tyrosine phosphatases

remove phosphoryl grpups from Tyr residues on the insulin receptor and the IRS adaptor proteins

Protein serine phosphatases

remove phosphoryl groups from activated protein kinases such as PKB

Lipid phosphatases

enzymes required to remove phosphoryl groups from inositol lipids such as PIP₃