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Chapter 40: Mechanisms of Signal Transduction

You are studying the responses of adipocytes in culture following their exposure to γ-irradiation. In comparison to normal adipocytes you find that when glucagon is added, the normal cells release free fatty acids to the medium but the irradiated cells do not. Binding studies show that both cell populations bind the same amount of glucagon with the same dissociation kinetics, indicating the receptors on the irradiated cells are unchanged. Given these results, which of the following proteins is most likely to be defective in the irradiated cells?

A. a Gq-type G-protein

B. a Gs-type G-protein

C. phosphatidic acid phosphatase

D. phosphatidylinositol-3-kinase (PI3K)

E. protein kinase C (PKC)

Answer B: When glucagon binds its receptor on adipocytes, it activates an associated Gs-type G-protein. The activated G-protein in turn activates adenylate cyclase, which catalyzes the synthesis of cAMP from ATP. The cAMP binds to the regulatory subunits of protein kinase A (PKA), resulting in release of the catalytic subunits. One of the targets of PKA is the enzyme, hormone-sensitive lipase, HSL, which is activated by PKA-mediated phosphorylation. Activation of HSL results in increased release of fatty acid from stored triglycerides.

You are studying the responses of myocytes in culture following their exposure to γ-irradiation. In a comparison to normal myocytes you find that when insulin is added, the normal cells actively take up glucose but the irradiated cells do not. Binding studies show that both cell populations bind the same amount of insulin with the same dissociation kinetics, indicating the receptors on the irradiated cells are unchanged. Given these results, which of the following proteins is most likely to be defective in the irradiated cells?

A. a Gq-type G-protein

B. a Gs-type G-protein

C. phosphatidic acid phosphatase

D. phosphatidylinositol-3-kinase (PI3K)

E. protein kinase A (PKA)

Answer D: In most nonhepatic tissues, insulin increases glucose uptake by increasing the number of plasma membrane glucose transporters, specifically GLUT4 in muscle cells. Insulin action leads to an increase in the activity of PI3K, which in turn phosphorylates membrane phospholipids generating phosphatidylinositol-3,4,5-trisphophate (PIP3) from phosphatidylinositol-4,5-bisphosphate (PIP2). PIP3 then activates the kinase PDK1, which in turn phosphorylates and activates a protein kinase C isoform (PKC-ζ) involved in the mobilization of GLUT4 to the plasma membrane. Loss of PI3K activation or activity would, therefore, result in reduced capacity to ...

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