99. Physiology | Signal Transduction II

A 68‑year‑old man with stable angina self‑administers sublingual nitroglycerin during chest pain. Minutes later he collapses after also taking sildenafil obtained from a friend. Paramedics note profound hypotension and reflex tachycardia. The additive effect of these two drugs is best explained by which of the following molecular events in vascular smooth muscle?

A. Persistent activation of phospholipase C and excess inositol trisphosphate
B. Excessive inhibition of phosphodiesterase‑5 leading to elevated cGMP
C. Sustained phosphorylation of receptor tyrosine kinases on the endothelium
D. Constitutive activation of the Ras‑MAP kinase cascade in arteriolar muscle
E. Overproduction of diacylglycerol with protein‑kinase C activation

B

Choice	Mechanism	Evaluation
A	Persistent PLC → ↑IP₃	Unrelated to NO‑cGMP pathway. ❌
B	Excessive inhibition of PDE‑5 → ↑cGMP	Both drugs raise cGMP (NO makes it, sildenafil blocks its breakdown) → profound vasodilation. ✅
C	Sustained RTK phosphorylation	RTKs are not involved here. ❌
D	Constitutive Ras‑MAPK activation	A growth‑signal, not an acute vasodilator. ❌
E	Overproduction of DAG	DAG is from PLC; not relevant. ❌

A patient with metastatic renal‑cell carcinoma is started on everolimus, an mTOR inhibitor. Two weeks later he reports delayed wound healing and oral ulcers. Everolimus most directly blocks which signaling step downstream of receptor tyrosine kinases?

A. Autophosphorylation of the insulin receptor β‑subunit
B. Conversion of PIP₂ to IP₃ and DAG by phospholipase C‑γ
C. Serine/threonine kinase that promotes protein synthesis and inhibits autophagy
D. Small‑G‑protein exchange of GDP for GTP that activates Raf
E. Tyrosine phosphorylation of STAT proteins in the JAK‑STAT pathway

C

Choice	Mechanism	Evaluation
A	Insulin‑RTK autophosphorylation	Upstream of PI3K, not mTOR itself. ❌
B	PLC‑γ generation of IP₃/DAG	Separate signaling arm. ❌
C	Ser/Thr kinase that drives protein synthesis & blocks autophagy (mTOR)	Everolimus directly inhibits mTOR. ✅
D	Ras GDP→GTP exchange	Ras is upstream in MAPK, unaffected by everolimus. ❌
E	STAT phosphorylation	JAK‑STAT pathway, not PI3K‑Akt‑mTOR. ❌

A 57‑year‑old woman with systemic sclerosis develops progressive pulmonary fibrosis. Biopsy shows excessive signaling through receptors that phosphorylate serine and threonine residues after dimerization. Which receptor type is most directly implicated in this fibrotic process?

A. Receptor guanylyl cyclase (GC‑A)
B. Receptor tyrosine kinase
C. Receptor serine/threonine kinase
D. Tyrosine‑kinase–associated (JAK‑coupled) receptor
E. Receptor tyrosine phosphatase

C

Tie‑in: TGF‑β receptor signaling via serine/threonine phosphorylation is central to fibrosis. ​

Choice	Mechanism	Evaluation
A	GC‑A (ANP/BNP)	Guanylyl cyclase, not fibrotic. ❌
B	RTK	Tyrosine kinases, not TGF‑β–like receptors. ❌
C	Receptor serine/threonine kinase	TGF‑β receptors (ser/thr kinases) drive fibrotic gene programs. ✅
D	JAK‑coupled receptor	Cytokine receptors; mainly immune modulation. ❌
E	RT phosphatase	Removes phosphates; opposite effect. ❌

A molecular‑biology lab creates a mutant Ras protein lacking intrinsic GTPase activity. When expressed in cultured epithelial cells, which of the following downstream effects is most likely to be observed?

A. Diminished activation of PI‑3‑kinase with reduced Akt phosphorylation
B. Enhanced and sustained ERK (MAP kinase) phosphorylation promoting proliferation
C. Reduced recruitment of adaptor protein Grb2 to the plasma membrane
D. Increased degradation of cGMP via phosphodiesterase‑5 activation
E. Constitutive stimulation of cytoplasmic steroid‑hormone receptors

B

Choice	Mechanism	Evaluation
A	↓Akt phosphorylation	Constitutively active Ras does not suppress PI3K/Akt. ❌
B	Sustained ERK (MAPK) phosphorylation → proliferation	Ras locked “ON” keeps Raf→MEK→ERK active. ✅
C	Less Grb2 recruitment	Mutant Ras is downstream of Grb2; recruitment unchanged. ❌
D	↑cGMP breakdown	PDE‑5/cGMP pathway unrelated. ❌
E	Stimulates steroid receptors	Nuclear receptors are separate signaling systems. ❌

Tie‑in: Ras–MAPK cascade drives growth; GTPase loss leads to oncogenic signaling.

A nephrology researcher notes that aldosterone can rapidly (within minutes) increase sodium reabsorption in collecting‑duct principal cells—an effect too fast to depend on gene transcription. Which of the following best explains this rapid “nongenomic” action of a steroid hormone?

A. Binding of aldosterone to a seven‑transmembrane GPCR coupled to Gₛ
B. Activation of membrane‑localized mineralocorticoid receptors within caveolae
C. Direct stimulation of soluble guanylyl cyclase to raise intracellular cGMP
D. Tyrosine‑kinase–mediated phosphorylation of ENaC channels
E. Inhibition of PI‑3‑kinase signaling to reduce Akt activity

B

Choice	Mechanism	Evaluation
A	7‑pass GPCR (Gs)	Aldosterone is a steroid; GPCR‑Gs is for peptides/catecholamines. ❌
B	Membrane‑localized mineralocorticoid receptors (caveolae)	Explains “nongenomic” steroid actions within minutes. ✅
C	Soluble GC activation	NO pathway, not aldosterone. ❌
D	Tyrosine‑kinase phosphorylation via JAK‑STAT	Cytokine signaling, not steroids. ❌
E	PI3K inhibition	Opposite of observed stimulation. ❌

Tie‑in: Steroid hormones have both genomic (hours) and rapid membrane‑receptor effects. ​Lecture 99 - Physiology