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Unformatted text preview: 1 Lecture #3: 1-12-2010 Lecture Outline: Membrane Bound Receptors: GPCRs, continued G s , G i , G q , G o Growth Factor Receptors: Intrinsic Tyrosine Kinase Activity Cytokine Receptors: Recruit Soluble Tyrosine Kinases Natriuretic Peptide Receptors Intracellular Receptors: Cytoplasmic: HSP-Associated Nuclear: Not associated with HSPs When the GPCR Pathway Fails: Cholera and Pertussis Cholera is a bacterial toxin that acts on the Gα subunit of the G protein coupled to the GPCR receptor. Specifically, cholera acts as an enzyme that catalyzes the ADP ribosylation of the G protein so that an ADP ribose group is covalently added to the Gα subunit. This reaction leads to irreversible loss of the Gα subunit’s intrinsic GTPase activity. Cholera is notorious for the effects it exerts in the intestines, which are made up of epithelial cells that have GPCRs linked to the Gα s pathway, which, when activated, results in increased cytosolic cAMP levels. The intestinal epithelial cells are one in several cell types that express the C ystic F ibrosis T ransmembrane R egulator channel (CFTR channel). The CFTR channel is a cAMP gated chloride channel that is dysfunctional in patients suffering from Cystic Fibrosis. In addition to the intestinal epithelial cell, the CFTR channel can be found in the colon, sweat glands, pancreatic duct, and lung. Additionally, it can be located on either the basolateral or apical side of the epithelial cell, depending on the cell type. For example, in intestinal cells, the CFTR channel is found in the apical membrane (Refer to Figure 21-9 in Silverthorn), where it allows for chloride excretion. Similarly, in the pancreas and lungs, the CFTR channel is located on the apical membrane and in individuals with cystic fibrosis the mucous secretions are very thick since there is little electrolyte and fluid secretion to dilute the mucous. In contrast, the CFTR channel is located on the basolateral membrane in the epithelial cells of the sweat gland ducts. In cystic fibrosis, this leads to a buildup of chloride within the sweat gland cell which leads to the excretion of Cl- (and in turn Na + ). Thus, cystic fibrosis patients have extremely salty sweat and this fact was used to diagnose babies born with the disease (“the sweat test”). When the cholera toxin induces the irreversible covalent ribosylation of the Gα s subunit, the cytosolic cAMP levels rise excessively. The cAMP molecules act on the ligand gated CFTR channels and keep them open for a longer period of time. This, in turn, results in increased Cl- excretion into the intestinal lumen. The increased Cl- excretion builds up a negative charge (electrical gradient) in the intestinal lumen that attracts Na + , thus leading to Na + excretion as well....
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This note was uploaded on 04/06/2012 for the course BICD 150 taught by Professor Fortes during the Winter '09 term at UCSD.
- Winter '09