A 17-year-old boy who was recently diagnosed with type 1 diabetes mellitus is found unresponsive at home. His family reports that the patient did not feel good last night and skipped dinner, but he still took his usual dose of insulin. Paramedics find that his fingerstick blood glucose is 32 mg/dL and immediately administer intramuscular glucagon. Glucagon binds to a transmembrane receptor in hepatocytes, which promotes binding of intracellular GTP to a specific receptor-associated protein. This leads to further downstream signaling and rapid metabolic changes within hepatocytes, including a rapid decrease in intracellular glycogen stores and release of glucose into the blood. Which of the following is the most likely mediator responsible for these effects?

Question

A 17-year-old boy who was recently diagnosed with type 1 diabetes mellitus is found unresponsive at home.  His family reports that the patient did not feel good last night and skipped dinner, but he still took his usual dose of insulin.  Paramedics find that his fingerstick blood glucose is 32 mg/dL and immediately administer intramuscular glucagon.  Glucagon binds to a transmembrane receptor in hepatocytes, which promotes binding of intracellular GTP to a specific receptor-associated protein.  This leads to further downstream signaling and rapid metabolic changes within hepatocytes, including a rapid decrease in intracellular glycogen stores and release of glucose into the blood.  Which of the following is the most likely mediator responsible for these effects?

Quizplus · Accepted Answer

11ec160b_36ce_dafe_9249_0b9db204878c_MD0001_00 Glucagon exerts its effects through G protein-coupled receptors using the adenylate cyclase second messenger system. G protein is a heterotrimer consisting of alpha, beta, and gamma subunits associated with the intracellular domain of these transmembrane receptors. The alpha subunit of the inactivated G protein is bound to GDP. On receptor activation, the alpha subunit undergoes a conformational change, which releases GDP and binds GTP. GTP binding allows the alpha subunit to dissociate from the remainder of the G protein complex. There are multiple subtypes of alpha G proteins, each with different secondary effects. A specific alpha subunit known as G_s (present in glucagon, TSH, and PTH receptor complexes) activates adenylate cyclase when released from the G protein complex. Adenylate cyclase converts ATP to cAMP, which activates protein kinase A. Protein kinase A phosphorylates specific serine/threonine residues in various enzymes, leading to their activation or deactivation. Protein kinase A also phosphorylates proteins that bind to the regulatory regions of genes on DNA. (Choice A) cGMP activates protein kinase G, which mediates a number of intracellular effects (eg, smooth muscle relaxation, platelet activation, sperm metabolism). cGMP is inactivated by cGMP phosphodiesterase, which cleaves cGMP in the corpus cavernosum of the penis and regulates penile erection. Drugs that inhibit cGMP-specific phosphodiesterase (eg, sildenafil) are used in the treatment of erectile dysfunction. (Choice B) Janus tyrosine kinase (JAK) is a cytoplasmic protein activated by ligand binding to non-G protein-coupled transmembrane receptors that lack intrinsic tyrosine kinase activity. Growth hormone, erythropoietin, and cytokines (eg, interferon) are common ligands for these receptors. JAKs activate cytoplasmic transcription factors called STATs (signal transducers and activators of transcription), which enter the nucleus to promote gene transcription. (Choice C) cAMP is cleaved by the enzyme cAMP phosphodiesterase to its inactive form, 5'-AMP. Drugs that inhibit cAMP phosphodiesterase lead to prolongation of the actions of cAMP. An example is the use of theophylline in bronchial asthma. (Choice E) Ligands such as insulin and epidermal growth factor act through transmembrane receptors that have intrinsic tyrosine kinase domains. Educational objective: Protein kinase A is responsible for the intracellular effects of the G protein-mediated adenylate cyclase second messenger system. Hormone receptors that use this system include the TSH, glucagon, and PTH receptors. __________ References: Glucagon receptors. (http://www.ncbi.nlm.nih.gov/pubmed/18292967)

A 17-Year-Old Boy Who Was Recently Diagnosed with Type 1