WBR235

Author	[[PageAuthor::Gerald Chi (Reviewed by Yazan Daaboul, M.D.)]]
Exam Type	ExamType::USMLE Step 1
Main Category	MainCategory::Physiology
Sub Category	SubCategory::Cardiology
Prompt	[[Prompt::A lab researcher develops a novel pharmacologic agent that preferentially targets smooth muscle cells in the coronary vessels. During her experiment, she accidentally sticks herself with a needle loaded with the novel agent, and she begins to have repeated attacks of profound substernal discomfort that prompt urgent evaluation in the emergency department (ED). In the ED, her vital signs are within normal range, and her physical examination is unremarkable. A 12-lead ECG demonstrates modest ST-segment elevation. Which of the following molecular events is most likely to be induced by the novel pharmacologic agent?]]
Answer A	AnswerA::Activation of protein kinase A
Answer A Explanation	AnswerAExp::Protein kinase A mediates the phosphorylation of the myosin light chain kinase and subsequently inactivates it. Myosin light chain kinase inactivation results in vasodilation.
Answer B	AnswerB::Activation of protein kinase G
Answer B Explanation	AnswerBExp::Activation of protein kinase G activates myosin light chain phosphatase. Activation of myosin light chain phosphatase results in vasodilation.
Answer C	AnswerC::Activation of phospholipase C
Answer C Explanation	[[AnswerCExp::In the classical muscle contraction pathway, stimuli (e.g. histamine) initially bind to Gq protein-coupled receptors located on the surface of vascular smooth muscle cells. The binding process activates phospholipase C, which mediates the synthesis of both 1,4,5-triphosphate (IP3) and diacylglycerol (DAG). IP3 then binds to receptors on the sarcoplasmic reticulum to mediate the mobilization of stored calcium into the cytosol. As cytosolic calcium concentration increases, calcium/calmodulin complexes form and activate MLCK, which result in the phosphorylation of myosin light chain and smooth muscle contraction.]]
Answer D	AnswerD::Inhibition of calcium binding to the troponin C subunit
Answer D Explanation	AnswerDExp::Calcium binding to the troponin C subunit is involved in the contraction of cardiac muscles rather than smooth muscles.
Answer E	AnswerE::Decreased expression of the gene that encodes phosphodiesterase 5
Answer E Explanation	AnswerEExp::Phosphodiesterase 5 converts cyclic GMP to 5'-GMP. Cyclic GMP activates protein kinase G and causes vasodilation.
Right Answer	RightAnswer::C
Explanation	[[Explanation::The novel agent induces an acute vasoconstriction of the epicardial coronary arteries and may result in either near or complete arterial occlusions. Coronary artery spasm typically manifests in angina with ST-segment elevations (not depressions) on 12-lead ECG. Modulation of contraction and relaxation of vascular smooth muscles is mainly mediated by the phosphorylation and dephosphorylation of myosin light chain kinase (MLCK) and phosphatase (MLCP). In the classical muscle contraction pathway, stimuli (e.g. histamine) initially bind to Gq protein-coupled receptors located on the surface of vascular smooth muscle cells. The binding process activates phospholipase C, which mediates the synthesis of both 1,4,5-triphosphate (IP3) and diacylglycerol (DAG). IP3 then binds to receptors on the sarcoplasmic reticulum to mediate the mobilization of stored calcium into the cytosol. As cytosolic calcium concentration increases, calcium/calmodulin complexes form and activate MLCK, which result in the phosphorylation of myosin light chain and smooth muscle contraction. Educational Objective: In the classical muscle contraction pathway, stimuli (e.g. histamine) initially bind to Gq protein-coupled receptors located on the surface of vascular smooth muscle cells. The binding process activates phospholipase C, which mediates the synthesis of both 1,4,5-triphosphate (IP3) and diacylglycerol (DAG). IP3 then binds to receptors on the sarcoplasmic reticulum to mediate the mobilization of stored calcium into the cytosol. As cytosolic calcium concentration increases, calcium/calmodulin complexes form and activate MLCK, which result in the phosphorylation of myosin light chain and smooth muscle contraction. References: Lanza GA, Careri G, Crea F. Mechanisms of coronary artery spasm. Circulation. 2011;124:1774-82. Kimura K, Ito M, Amano M, et al. Regulation of myosin phosphatase by Rho and Rho-associated kinase (Rho-kinase). Science. 1996;273(5272):245-8. Somlyo AP, Somlyo AV. Signal transduction and regulation in smooth muscle. Nature. 1994; 372(6503):231-6.]]
Approved	Approved::Yes
Keyword	WBRKeyword::Vasospasm, WBRKeyword::Coronary artery spasm, WBRKeyword::Muscle contraction, WBRKeyword::Pharmacologic agent, WBRKeyword::Phospholipase C, WBRKeyword::PIP2, WBRKeyword::IP3, WBRKeyword::DAG, WBRKeyword::Calcium, WBRKeyword::MLCK, WBRKeyword::MLCP, WBRKeyword::Classical muscle contraction pathway
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