L3

I. Introduction to Second Messenger Mechanisms: Which hormones activate second messenger pathways?

Water-soluble hormones

I. Introduction to Second Messenger Mechanisms: How do these hormones cause intracellular effects?

By binding to plasma membrane receptors → activate second messenger systems inside the cell

I. Introduction to Second Messenger Mechanisms: What is the hormone’s only direct action?

Activating a specific membrane receptor

I. Introduction to Second Messenger Mechanisms: Who carries out the intracellular effects?

The second messenger

I. Introduction to Second Messenger Mechanisms: Can a hormone activate more than one second messenger system in the same tissue?

Yes

II. Types of Second Messengers: What are the 3 major types of second messengers?

1. Ca²⁺ ions + calmodulin
2. Membrane phospholipid breakdown products
3. cAMP

II. Types of Second Messengers: What protein mediates calcium’s intracellular effects?

Calmodulin

II. Types of Second Messengers: What is special about membrane phospholipid breakdown?

It can stimulate multiple second messenger systems simultaneously

III. G Protein and Effector Protein Mechanism: What happens when a ligand binds its receptor?

It activates the G protein

III. G Protein and Effector Protein Mechanism: Which part of the G protein interacts with the effector protein?

The alpha (α) subunit

III. G Protein and Effector Protein Mechanism: What does the effector protein do?

Increases intracellular second messenger concentration

III. G Protein and Effector Protein Mechanism: How do second messengers cause cellular changes?

They activate protein kinases that trigger phosphorylation cascades

III. G Protein and Effector Protein Mechanism: What receptors are used by most second messenger systems?

G-protein coupled receptors (GPCRs)

IV. Adenylyl Cyclase – cAMP Pathway: What enzyme does Gs activate?

Adenylyl cyclase

IV. Adenylyl Cyclase – cAMP Pathway: What does adenylyl cyclase do?

Converts ATP → cAMP

IV. Adenylyl Cyclase – cAMP Pathway: What kinase is activated by cAMP?

Protein kinase A (PKA)

IV. Adenylyl Cyclase – cAMP Pathway: How does PKA cause a cellular response?

Phosphorylates target proteins → biochemical changes

IV. Adenylyl Cyclase – cAMP Pathway: How does PKA affect transcription?

Enters nucleus → phosphorylates CREB → binds CRE → gene transcription

IV. Adenylyl Cyclase – cAMP Pathway: What inhibits adenylyl cyclase?

Gi protein

IV. Adenylyl Cyclase – cAMP Pathway: Hormones that use the cAMP pathway:

ACTH, Ang II (epithelial), Calcitonin, Catecholamines (β), CRH, FSH, Glucagon, GHRH, hCG, LH, PTH, Secretin, Somatostatin, TSH, Vasopressin (V2)

V. Guanylyl Cyclase – cGMP Pathway: What substrate is converted into cGMP and by what enzyme?

GTP → cGMP by guanylyl cyclase

V. Guanylyl Cyclase – cGMP Pathway: What does cGMP activate?

cGMP-dependent protein kinases (PKG)

V. Guanylyl Cyclase – cGMP Pathway: Key example of cGMP use?

Phototransduction in rod cells (rhodopsin receptors)

VI. Phospholipase C – PIP₂ Pathway: What G-protein activates PLC?

Gq

VI. Phospholipase C – PIP₂ Pathway: What enzyme starts this pathway?

Phospholipase C (PLC)

VI. Phospholipase C – PIP₂ Pathway: What membrane phospholipid does PLC act on?

PIP₂ (phosphatidylinositol 4,5-bisphosphate)

VI. Phospholipase C – PIP₂ Pathway: What are the products of PIP₂ hydrolysis?

1. IP₃ → cytosol → Ca²⁺ release from ER
2. DAG → remains in membrane → activates PKC

VI. Phospholipase C – PIP₂ Pathway: What does PKC do?

Phosphorylates proteins → cellular responses
Activates MAP kinase cascade (gene expression)

VI. Phospholipase C – PIP₂ Pathway: How do IP₃ and DAG work together in contraction?

IP₃ → Ca²⁺ release → contraction
DAG → PKC → ↑ Ca²⁺ sensitivity → stronger contraction

VI. Phospholipase C – PIP₂ Pathway: Hormones using the PLC pathway:

Ang II (smooth muscle), Catecholamines (α), GnRH, GHRH, PTH, Oxytocin, TRH, Vasopressin (V1)

VII. Detailed PIP₂ Pathway Mechanism: Where is PIP₂ located?

Inner leaflet of plasma membrane (minor phospholipid)

VII. Detailed PIP₂ Pathway Mechanism: What stimulates PIP₂ hydrolysis?

Ligand binding → activates PLC

VII. Detailed PIP₂ Pathway Mechanism: Which receptors activate PLC?

GPCRs → activate PLC-β via Gq
Tyrosine kinase receptors → activate PLC-γ via SH2 domains

VIII. Calcium-Calmodulin System: How can Ca²⁺ enter the cell?

1. Voltage-gated Ca²⁺ channels (depolarization)
2. Ligand-gated channels (hormone-activated)

VIII. Calcium-Calmodulin System: What protein does Ca²⁺ bind to?

Calmodulin

VIII. Calcium-Calmodulin System: How many Ca²⁺ ions must bind calmodulin?

3 or 4 ions

VIII. Calcium-Calmodulin System: What happens after binding?

Conformational change → activation

VIII. Calcium-Calmodulin System: What does Ca²⁺-calmodulin complex activate?

Calmodulin-dependent kinases (CaM kinases) or other kinases

VIII. Calcium-Calmodulin System: How is CaM kinase activation like PKA?

Both are activated by second messengers (Ca²⁺-calmodulin vs. cAMP)
Both activate kinases → protein phosphorylation

IX. Calcium and Neurotransmission: Other ways Ca²⁺ increases in the cell:

Presynaptic depolarization → Ca²⁺ influx → vesicle fusion and NT release
AP → Ca²⁺ release from ER via IP₃
Ca²⁺ binds calmodulin/actin-myosin → muscle contraction

IX. Calcium and Neurotransmission: What does IP₃ stimulate in calcium signaling?

Releases Ca²⁺ from ER

IX. Calcium and Neurotransmission: How does Ca²⁺ affect actin-myosin?

Triggers sliding for contraction

IX. Calcium and Neurotransmission: Role of calcium in presynaptic terminals?

Triggers vesicle fusion → NT release

X. Examples of Second Messenger Systems: How does epinephrine use both cAMP and Ca²⁺-calmodulin?

β-adrenergic: GPCR → cAMP → PKA → glucose mobilization
α-adrenergic: Ca²⁺/calmodulin → kinases → glucose release

X. Examples of Second Messenger Systems: Epinephrine cAMP result in liver cells?

PKA → glucose 1-phosphate → glucose 6-phosphate → free glucose
→ glycogenolysis

X. Examples of Second Messenger Systems: How does ACh use the PLC pathway in smooth muscle?

ACh → GPCR → PLC → PIP₂ → IP₃ & DAG
→ IP₃ → Ca²⁺ → calmodulin → NO synthase → NO → guanylyl cyclase → cGMP → PKG → relaxation

X. Examples of Second Messenger Systems: Role of NO in signaling?

Second messenger that stimulates cGMP → activates PKG → smooth muscle relaxation

XI. Amplification of Signal: How can a small hormone amount cause a big effect?

Second messenger cascades amplify the signal at every step

XI. Amplification of Signal: General result of second messenger pathways?

1 hormone → many messengers → activate thousands of molecules → large response

XI. Amplification of Signal: Examples of kinases acting as gene regulators:

PKA
CaM-kinase
PKC
MAP-kinase
PKB
PDK1