L2

What is signal transduction?

A process where extracellular ligands bind to receptors, initiating intracellular signaling events that lead to a specific cellular response.

What is the starting signal and final outcome of signal transduction?

Starting signal: ligand (extracellular chemical messenger)
Final outcome: intracellular response (e.g., gene expression, protein synthesis)

Where does signal transformation occur?

Inside the target cell

What are the 3 locations of hormone receptors?

1. On the plasma membrane
2. In the cytosol
3. In the nucleus

Which hormones bind at each receptor location?

Plasma membrane: Water-soluble (peptides, proteins, catecholamines)
Cytosol: Steroid hormones
Nucleus: Thyroid hormones

How do hormones affect their target cells?

They bind to receptors → form hormone-receptor complex → triggers cellular signaling response

Lipid-soluble messengers

Steroids → bind intracellular receptors → gene expression via protein kinases

Water-soluble messengers

Catecholamines, peptides, proteins, neurotransmitters → bind membrane receptors

Pathways for Water-Soluble Messengers: Ligand-Gated Ion Channel Pathway

Ligand (e.g., Ach) binds → channel opens → ion flow → membrane potential changes

Pathways for Water-Soluble Messengers: GPCR Pathway

Ligand binds GPCR → G-protein activated → second messengers (e.g., cAMP) produced → cellular response

Pathways for Water-Soluble Messengers: Receptor-Enzyme Complex Pathway

Ligand binds receptor-enzyme → enzymatic activity activated (e.g., insulin, growth factors)

GPCR Signaling Details: What happens when a hormone binds to a GPCR?

→ GPCR undergoes conformational change → activates G-protein (GDP replaced with GTP)

What are the G-protein subunits and their roles?

Gα: Activated by GTP, dissociates and activates/inhibits effector proteins
Gβγ: Can also regulate ion channels and enzymes

What are the Gα isoforms and their actions?

Gαs: Stimulates adenylyl cyclase → ↑ cAMP
Gαi: Inhibits adenylyl cyclase → ↓ cAMP

What is the effector protein in GPCR signaling?

A membrane-bound protein (e.g., adenylyl cyclase) altered by Gα → increases second messengers like cAMP

How is GPCR signaling turned off?

Gα has intrinsic GTPase activity → GTP → GDP → rebinds βγ → signal stops
Phosphodiesterase degrades cAMP → AMP

What activates enzyme-linked receptors?

Hormone binding to extracellular domain → activates cytoplasmic enzyme domain

What are the two main types of enzyme-linked pathways?

1. Tyrosine kinase receptors
2. JAK/STAT pathway

Tyrosine Kinase Pathway: How do tyrosine kinase receptors work?

Ligand binding → receptor dimerization → autophosphorylation → activates downstream signaling proteins → cellular effects

Hormones that use tyrosine kinase signaling:

Insulin
IGF-1
GH
FGF
EGF
HGF
Leptin (partly JAK/STAT)
VEGF

What is the structure and function of the insulin receptor?

Composed of 2 α and 2 β subunits (dimer)
Insulin binds → autophosphorylation of β-subunits → activates TK domain
Results: glucose uptake (GLUT-4), anabolic processes (protein/fat/glycogen synthesis)

JAK/STAT Pathway: How does JAK/STAT signaling work?

Ligand binds receptor → JAKs phosphorylate STATs → STATs dimerize → enter nucleus → gene transcription

Where is the tyrosine kinase activity located in the JAK/STAT pathway?

On JAKs (cytosolic side of receptor)

What gets phosphorylated in the JAK/STAT pathway?

STAT proteins (Signal Transducer and Activator of Transcription)

Where do phosphorylated STATs go in the JAK/STAT pathway?

Into the nucleus → initiate transcription → protein synthesis → cellular response

Which hormones use the JAK/STAT pathway?

Cytokines
ProLactin
Leptin

Leptin Receptor Function: What is the leptin receptor structure?

Homodimer (2 identical subunits)

What hormone activates the leptin receptor?

Leptin (secreted by fat cells)

What kinase does the leptin receptor activate?

JAK2

Leptin Receptor Function: What happens after activation?

JAK2 phosphorylates STATs → STATs enter nucleus → initiate transcription
Also activates other enzymes for rapid leptin effects (e.g., appetite suppression)

What is leptin's role?

Regulates appetite and energy expenditure; secreted by adipocytes

I. Intracellular receptor pathway

Lipophilic hormones cross membrane → bind cytosolic/nuclear receptor → gene transcription (e.g., cortisol, thyroid hormone)

II. Ion-channel-linked receptor

Ligand-gated channels open/close → ion flow → change in membrane potential (e.g., Ach on Na+ channel)

III. GPCR and second messenger pathway

Ligand binds GPCR → G-protein activated (α-GTP) → effector enzyme activated → second messenger produced (e.g., cAMP) → signal amplification

IV. Tyrosine kinase receptor pathway

Ligand binds RTK → dimerization → autophosphorylation → downstream activation → effects like metabolism, growth, gene expression (e.g., insulin)

V. JAK/STAT receptor pathway

Ligand binds → JAK activation → STAT phosphorylation → STAT dimer enters nucleus → transcription (e.g., leptin, cytokines)