Secondary messengers: cAMP, cGMP, Ca2+, IP3, NO, DAG MCQs With Answer

Introduction: Secondary messengers like cAMP, cGMP, Ca2+, IP3, NO and DAG are central to intracellular signal transduction, linking receptor activation to physiological responses. For M.Pharm students, mastering their generation, breakdown, receptors, downstream kinases and pharmacological modulators is vital for understanding drug actions and designing therapeutics. This quiz-focused resource emphasizes mechanistic depth: G‑protein coupling (Gs, Gi, Gq), enzymes (adenylyl/guanylyl cyclases, phospholipase C, phosphodiesterases, nitric oxide synthases), effector proteins (PKA, PKG, PKC, CaM kinases), and clinically relevant modulators (cholera/pertussis toxins, sildenafil). Each question tests conceptual and applied knowledge to prepare you for advanced exams and rational drug design of agents targeting these signaling pathways.

Q1. Which intracellular protein is the primary direct target of cAMP leading to phosphorylation of downstream substrates?

• Protein kinase C (PKC)
• Protein kinase A (PKA)
• Phosphodiesterase (PDE)
• Guanylyl cyclase (GC)

Correct Answer: Protein kinase A (PKA)

Q2. Which enzyme catalyzes the conversion of ATP to cyclic AMP (cAMP)?

• Guanylyl cyclase
• Adenylyl cyclase (adenylate cyclase)
• Phosphodiesterase
• Adenosine deaminase

Correct Answer: Adenylyl cyclase (adenylate cyclase)

Q3. Activation of which G protein α-subunit class stimulates adenylyl cyclase and increases cAMP?

• Gαi (inhibitory)
• Gαq
• Gαs (stimulatory)
• Gα12/13

Correct Answer: Gαs (stimulatory)

Q4. Cholera toxin increases intracellular cAMP by ADP‑ribosylating which G protein, locking it in an active state?

• Gαi
• Gαs
• Gβγ
• Gαq

Correct Answer: Gαs

Q5. What is the primary biochemical function of phosphodiesterases (PDEs) in cyclic nucleotide signaling?

• Convert cAMP to ATP
• Hydrolyze cAMP and cGMP to their non-cyclic nucleotide forms (AMP/GMP)
• Phosphorylate cyclic nucleotides
• Synthesize cGMP from GTP

Correct Answer: Hydrolyze cAMP and cGMP to their non-cyclic nucleotide forms (AMP/GMP)

Q6. Nitric oxide (NO) mediates vascular smooth muscle relaxation primarily by:

• Activating particulate guanylyl cyclase on the plasma membrane
• Activating soluble guanylyl cyclase (sGC) in the cytosol to raise cGMP
• Directly phosphorylating myosin light chain
• Inhibiting nitric oxide synthase

Correct Answer: Activating soluble guanylyl cyclase (sGC) in the cytosol to raise cGMP

Q7. Sildenafil enhances nitric oxide signaling and penile erection by selectively inhibiting which enzyme?

• Phosphodiesterase-4 (PDE4)
• Phosphodiesterase-3 (PDE3)
• Phosphodiesterase-5 (PDE5)
• Phosphodiesterase-1 (PDE1)

Correct Answer: Phosphodiesterase-5 (PDE5)

Q8. The IP3 receptor that mediates intracellular Ca2+ release is located primarily on which membrane?

• Plasma membrane
• Endoplasmic/sarcoplasmic reticulum membrane
• Mitochondrial outer membrane
• Golgi apparatus membrane

Correct Answer: Endoplasmic/sarcoplasmic reticulum membrane

Q9. Diacylglycerol (DAG) produced from PIP2 cleavage primarily activates which intracellular enzyme?

• Protein kinase A (PKA)
• Protein kinase C (PKC)
• Phospholipase A2 (PLA2)
• Soluble guanylyl cyclase (sGC)

Correct Answer: Protein kinase C (PKC)

Q10. Which enzyme hydrolyzes PIP2 into the second messengers IP3 and DAG?

• Phospholipase C (PLC)
• Phospholipase A2 (PLA2)
• Phospholipase D (PLD)
• PI3-kinase

Correct Answer: Phospholipase C (PLC)

Q11. Intracellular Ca2+ commonly exerts effects by binding which calcium sensor protein to activate downstream kinases such as CaMKII?

• Calmodulin
• Troponin C only
• Calsequestrin exclusively
• Calnexin

Correct Answer: Calmodulin

Q12. In rod photoreceptors, exposure to light leads to which immediate change in cGMP and membrane currents?

• Increase in cGMP and depolarization
• Decrease in cGMP and hyperpolarization
• No change in cGMP but increased transmitter release
• Increase in cGMP and increased Ca2+ influx

Correct Answer: Decrease in cGMP and hyperpolarization

Q13. The IP3 receptor and the ryanodine receptor are both intracellular Ca2+ release channels. Which statement correctly distinguishes their primary activation mechanisms?

• IP3 receptor is activated by IP3; ryanodine receptor is activated by cyclic AMP
• IP3 receptor is activated by IP3; ryanodine receptor is activated primarily by Ca2+‑induced Ca2+ release (CICR)
• Both are activated exclusively by DAG
• Both are activated by nitric oxide

Correct Answer: IP3 receptor is activated by IP3; ryanodine receptor is activated primarily by Ca2+‑induced Ca2+ release (CICR)

Q14. Classical (conventional) PKC isoforms require which cofactors for activation at the membrane?

• cAMP only
• DAG only
• DAG and Ca2+
• NO and cGMP

Correct Answer: DAG and Ca2+

Q15. Nitric oxide synthase (NOS) produces NO from which substrate?

• L-Arginine
• L-Glutamate
• L-Lysine
• L-Serine

Correct Answer: L-Arginine

Q16. cGMP-dependent protein kinase (PKG) promotes smooth muscle relaxation primarily by which mechanism?

• Phosphorylating and activating myosin light chain kinase (MLCK)
• Increasing intracellular Ca2+ concentration
• Activating myosin light chain phosphatase (MLCP) leading to MLC dephosphorylation
• Directly hydrolyzing ATP to AMP

Correct Answer: Activating myosin light chain phosphatase (MLCP) leading to MLC dephosphorylation

Q17. Pertussis toxin increases cAMP in some cells by ADP‑ribosylating which G protein, preventing its inhibitory effect on adenylyl cyclase?

• Gαs
• Gαi
• Gαq
• Gβγ complex

Correct Answer: Gαi

Q18. Which phosphodiesterase isoform has the highest selectivity for hydrolyzing cGMP and is the primary target of drugs used to potentiate NO signaling?

• PDE3
• PDE4
• PDE5
• PDE2

Correct Answer: PDE5

Q19. Which listed messenger is gaseous, freely diffuses across membranes, and acts on nearby cells rather than via membrane-bound receptors?

• IP3
• cAMP
• Nitric oxide (NO)
• DAG

Correct Answer: Nitric oxide (NO)

Q20. How does cAMP activate protein kinase A (PKA) at the molecular level?

• cAMP phosphorylates the catalytic subunits directly
• cAMP binds the regulatory subunits causing release and activation of catalytic subunits
• cAMP degrades the regulatory subunits via proteolysis
• cAMP converts ATP to ADP which activates PKA

Correct Answer: cAMP binds the regulatory subunits causing release and activation of catalytic subunits

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