A 59-year-old man is brought to the emergency department one hour after developing shortness of breath and “squeezing” chest pain that began while he was mowing the lawn. He has asthma, hypertension, and erectile dysfunction. Current medications include salmeterol, amlodipine, lisinopril, and vardenafil. His pulse is 110/min and blood pressure is 122/70 mm Hg. Physical examination shows diaphoresis. An ECG shows sinus tachycardia. Sublingual nitroglycerin is administered. Five minutes later, his pulse is 137/min and his blood pressure is 78/40 mm Hg. Which of the following is the most likely mechanism of this patient's hypotension?

Decreased nitric oxide production

A 70-year-old male presents to his primary care provider complaining of decreased sexual function. He reports that over the past several years, he has noted a gradual decline in his ability to sustain an erection. He used to wake up with erections but no longer does. His past medical history is notable for diabetes, hyperlipidemia, and a prior myocardial infarction. He takes metformin, glyburide, aspirin, and atorvastatin. He drinks 2-3 drinks per week and has a 25 pack-year smoking history. He has been happily married for 40 years. He retired from his job as a construction worker 5 years ago and has been enjoying retirement with his wife. His physician recommends starting a medication that is also used in the treatment of pulmonary hypertension. Which of the following is a downstream effect of this medication?

Decrease nitric oxide production

A 59-year-old man comes to the physician because of a 1-year history of increased urinary frequency, weak urinary stream, and occasional straining to void urine. Rectal examination shows a large, nontender prostate without asymmetry or nodularity. His serum creatinine, prostate-specific antigen, and urinalysis are all within the reference range. A diagnosis of benign prostatic hyperplasia is made, and treatment with tamsulosin is begun. Which of the following changes in intracellular messaging is most likely to occur in response to this drug?

Decreased activity of phospholipase C

Increased activity of protein kinase C

Increased production of diacylglycerol

Decreased activity of protein kinase A

Increased activity of adenylyl cyclase

A 55-year-old woman has a total thyroidectomy for papillary thyroid carcinoma. She complains of tingling around the mouth 11 hours after the operation. Her condition rapidly deteriorates with difficulty breathing and chest tightness. Which of the following best represent the signaling pathway of the deficient hormone responsible for this patient’s symptoms?

Cyclic adenosine monophosphate (cAMP)

Cyclic guanosine monophosphate (cGMP)

An investigator is studying the principles of cell-to-cell signaling of the autonomic nervous system. It is found that the adrenal medulla has receptors that, when activated, result in the immediate opening of Na+, Ca2+, and K+ channels, which subsequently leads to the secretion of epinephrine and norepinephrine. These receptors are structurally most similar to which of the following receptors?

NM receptors of the quadriceps femoris muscle

Alpha 1 receptors of the bladder neck

D2 receptors of the basal ganglia

An 11-month-old boy is brought to a pediatrician by his parents with a recurrent cough, which he has had since the age of 2 months. He has required 3 hospitalizations for severe wheezing episodes. His mother also mentions that he often has diarrhea. The boy’s detailed history reveals that he required hospitalization for meconium ileus during the neonatal period. Upon physical examination, his temperature is 37.0°C (98.6ºF), pulse rate is 104/min, respiratory rate is 40/min, and blood pressure is 55/33 mm Hg. An examination of the boy’s respiratory system reveals the presence of bilateral wheezing and scattered crepitations. An examination of his cardiovascular system does not reveal any abnormality. His length is 67.3 cm (26.5 in) and weight is 15 kg (33 lbs). His sweat chloride level is 74 mmol/L. His genetic evaluation confirms that he has an autosomal recessive disorder resulting in a dysfunctional membrane-bound protein. Which of the following best describes the mechanism associated with the most common mutation that causes this disorder?

Defective maturation and early degradation of the protein

Decreased chloride transport through the protein

Disordered regulation of the protein

Decreased transcription of the protein due to splicing defect

Complete absence of the protein

A research team discovers a novel bacterial toxin that causes severe hypotension in infected patients. In vitro studies show the toxin ADP-ribosylates a specific amino acid on Gq alpha subunits, preventing their activation by GPCRs. Patients develop hypotension despite elevated levels of vasopressin, angiotensin II, and endothelin-1. Synthesize the pathophysiological mechanism explaining why multiple vasopressor hormones fail to maintain blood pressure in these patients.

ADP-ribosylation of Gq prevents PLC activation, blocking IP3-mediated calcium release and vascular smooth muscle contraction

The toxin depletes intracellular ATP preventing myosin-actin interaction

The toxin prevents receptor binding of vasopressor hormones through allosteric inhibition

ADP-ribosylation increases cAMP levels causing smooth muscle relaxation

The toxin activates Gi proteins causing excessive vasodilation that overwhelms vasoconstrictor signals

Second messenger systems (cAMP, cGMP, Ca2+) — USMLE Lesson

Second Messengers - Cellular Gossip Girls

cAMP System (Gs/Gi): Ligand → Gs/Gi protein → Adenylyl Cyclase (AC) → ↑/↓cAMP → Protein Kinase A (PKA).
IP3/DAG System (Gq): Ligand → Gq protein → Phospholipase C (PLC) → PIP2 cleaved to IP3 + DAG.
- IP3 → ↑Ca²⁺ release from ER.
- DAG + Ca²⁺ → Protein Kinase C (PKC).
cGMP System: Nitric Oxide (NO) or ANP → Guanylyl Cyclase (GC) → ↑cGMP → Protein Kinase G (PKG).

⭐ Cholera Toxin permanently activates Gs by ADP-ribosylation, causing massive ↑cAMP, leading to severe secretory diarrhea.

cAMP and IP3/Ca2+ Second Messenger Pathways

cAMP Pathway - The 'On' Switch

Mechanism: Ligand binding to a Gs-protein coupled receptor (GPCR) triggers the exchange of GDP for GTP on the Gαs subunit.
Activation: The activated Gαs subunit dissociates and activates adenylyl cyclase.
Second Messenger: Adenylyl cyclase converts ATP to cyclic AMP (cAMP).
Effector: cAMP activates Protein Kinase A (PKA), which phosphorylates target proteins, causing a cellular response.

GPCR signaling pathways and second messengers

⭐ Cholera toxin permanently activates Gαs by ADP-ribosylation, leading to a massive ↑ in cAMP in intestinal cells. This causes continuous phosphorylation of the CFTR channel, resulting in severe secretory diarrhea.

📌 Mnemonic (Gs-coupled receptors): "FLAT ChAMP" - FSH, LH, ACTH, TSH, CRH, hCG, Adrenaline/Noradrenaline (β-receptors), MSH, PTH.

cGMP Pathway - The 'Relax' Signal

Activator: Nitric Oxide (NO) & natriuretic peptides (ANP, BNP).
Enzyme: Guanylate Cyclase (converts GTP → cGMP).
Effector: Protein Kinase G (PKG).

Mechanism of Action:

NO, often from endothelial cells or drugs like nitroglycerin, activates soluble guanylate cyclase.
↑ cGMP activates Protein Kinase G.
PKG activation leads to ↓ intracellular Ca²⁺ and activation of Myosin Light Chain Phosphatase.
Result: Smooth muscle relaxation → vasodilation.

Second messenger systems in smooth muscle contraction

⭐ Clinical Pearl: Phosphodiesterase-5 (PDE-5) inhibitors like sildenafil prevent the breakdown of cGMP, prolonging vasodilation. Co-administration with nitrates can cause life-threatening hypotension.

📌 Mnemonic: cGMP = Causes Generous Muscle Paralysis (relaxation).

IP₃/DAG/Ca²⁺ Pathway - The 'Release' Crew

Trigger: Ligand binds to a Gq-protein coupled receptor (GPCR).
Mechanism:
- Gq activates Phospholipase C (PLC).
- PLC cleaves membrane lipid PIP₂ into IP₃ (Inositol trisphosphate) and DAG (Diacylglycerol).
- IP₃ travels to the endoplasmic reticulum → triggers release of stored Ca²⁺.
- DAG and ↑Ca²⁺ co-activate Protein Kinase C (PKC) → cellular response via phosphorylation.

📌 Mnemonic (Gq receptors): "HAVe 1 M&M" → H₁, α₁, V₁, M₁, M₃.

⭐ Exam Favorite: Lithium, used for bipolar disorder, inhibits inositol monophosphatase, dampening this pathway by depleting recyclable inositol precursors.

High‑Yield Points - ⚡ Biggest Takeaways

G-protein coupled receptors (GPCRs) are central to second messenger signaling.

Gs (stimulatory) and Gi (inhibitory) modulate adenylyl cyclase to control cAMP levels, which in turn activates Protein Kinase A (PKA).

Gq activates phospholipase C, yielding IP₃ (releases intracellular Ca²⁺) and DAG (activates Protein Kinase C).

Nitric oxide (NO) stimulates guanylyl cyclase, increasing cGMP to cause smooth muscle relaxation.

Phosphodiesterases degrade cAMP/cGMP; inhibitors prolong their signals.

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