Signal II
High-yield summary: Second messenger systems
Based on your lecture PDF.
Physiolgy - Secondary messenger system.pdf
1. Core concept
First messenger: extracellular signal, such as a hormone or neurotransmitter.
Second messenger: intracellular molecule that carries the signal onward—cAMP, cGMP, IP₃, DAG, or Ca²⁺.
Second messengers activate enzymes and kinases, producing a cellular response and amplifying the original signal.
2. G proteins: the molecular switch
Heterotrimeric G proteins contain α, β, and γ subunits.
State/step | What happens |
Inactive | α binds GDP and associates with βγ |
Receptor activated | Ligand binds → GDP is exchanged for GTP |
Active | α–GTP and βγ regulate enzymes or ion channels |
Signal stops | α has GTPase activity: GTP → GDP |
Exam point: Both α and βγ can transmit signals.
3. The pathways you must distinguish
Pathway | Main sequence | Key target |
Gs | ↑ Adenylyl cyclase → ATP converted to cAMP | Protein kinase A (PKA) |
Gi | ↓ Adenylyl cyclase → ↓ cAMP | ↓ PKA activity |
Gq | Phospholipase C → PIP₂ split into IP₃ + DAG | Ca²⁺ release + PKC activation |
cGMP | Guanylyl cyclase → GTP converted to cGMP | Protein kinase G (PKG) |
Ca²⁺–calmodulin | ↑ Cytosolic Ca²⁺ → binds calmodulin | Calmodulin-dependent enzymes/kinases |
Memorize: cAMP → A; cGMP → G; DAG + Ca²⁺ → C.
4. cAMP pathway
Ligand → receptor → Gs → adenylyl cyclase → cAMP → PKA → protein phosphorylation → response
PKA can alter enzyme activity, ion channels, secretion, and gene expression.
Lecture example | High-yield effect |
ACTH → adrenal cortex | Stimulates steroid synthesis, especially cortisol |
Vasopressin → kidney | Through V₂ receptors, increases water reabsorption |
Glucagon → liver | ↑ Gluconeogenesis and glycogen breakdown; ↓ glycolysis → ↑ blood glucose |
Epinephrine → adipose tissue | Promotes lipolysis through β-adrenergic signaling |
Slide clarification: ACTH is primarily associated with cortisol regulation; aldosterone is mainly controlled by angiotensin II and plasma K⁺.
5. cGMP pathway
Guanylyl cyclase converts GTP → cGMP → activates PKG.
Signal | Guanylyl cyclase activated |
ANP—atrial natriuretic peptide | Membrane receptor guanylyl cyclase |
NO—nitric oxide | Soluble intracellular guanylyl cyclase |
Phosphodiesterase (PDE) breaks down cGMP to 5′-GMP, terminating the signal.
Protein phosphatases remove phosphate groups from target proteins.
Exam distinction: ANP and NO both use cGMP, but activate different forms of guanylyl cyclase.
6. IP₃–DAG pathway
Ligand → Gq → phospholipase C (PLC) → PIP₂ → IP₃ + DAG
Product | Location/action |
IP₃ | Moves through the cytosol → binds IP₃ receptors on the ER → releases Ca²⁺ |
DAG | Remains in the plasma membrane → together with Ca²⁺ activates conventional PKC |
Released Ca²⁺ | Acts as a second messenger and can bind calmodulin |
Important figure distinction: PLC can also be activated by a growth-factor receptor tyrosine kinase through PLC-γ. Therefore, PLC signaling is not limited to G proteins.
7. Calcium as a second messenger
Cytosolic Ca²⁺ rises through:
Entry from outside the cell through plasma-membrane Ca²⁺ channels.
Release from the ER through IP₃ receptors or ryanodine receptors.
Ca²⁺ → calmodulin → calmodulin-dependent protein kinase → protein phosphorylation → response
The ryanodine-receptor figure illustrates Ca²⁺-induced Ca²⁺ release: incoming calcium triggers additional calcium release from intracellular stores.
Final exam checklist
GDP = inactive; GTP = active.
α-subunit GTPase switches the G protein off.
Gs increases cAMP; Gi decreases cAMP.
cAMP activates PKA; cGMP activates PKG.
PLC splits PIP₂ into IP₃ and DAG.
IP₃ releases ER calcium; DAG stays in the membrane.
DAG + Ca²⁺ activate conventional PKC.
Ca²⁺ binds calmodulin to activate downstream enzymes.
ANP → membrane guanylyl cyclase; NO → soluble guanylyl cyclase.