This application seeks support through the Center for Membrane Toxicology Studies (CMTS) at the Mount Desert Island Biological Laboratory for studies on the effects of three heavy metals (cadmium, cobalt and nickel) on signal transduction pathways of hormones regulating chloride secretion in the shark rectal gland. The shark rectal gland is a homogenous, single cell type, highly specialized epithelium that is a model system for hormone regulated chloride secretion. Our hypothesis is that the toxic effects of heavy metals results from interactions at different specific sites of stimulatory as opposed to inhibitory hormonal signal transduction pathways. We have determined that cadmium reversibly blocks receptor-mediated inhibition of chloride secretion and that a major component of this effect occurs by a novel and unexpected mechanism- and augmentation of the response to stimulatory hormones. We will determine the specific site(s) of this metal-protein interaction by distinguishing between effects of cadmium on (a) an extracellular receptor for Cd mediating activation of inositol triphosphates and release of intracellular calcium; (b) direct effects on specific isozyme of cyclic nucleotide phosphodiesterases; and (c) a post-receptor/kinase mechanism- translocation of DFTR-chloride channels from an intracellular site to the apical plasma membrane. In contrast to Cd, cobalt and nickel inhibit VIP and forskolin stimulated chloride secretion in the perfused rectal gland. In collaboration with others in the center we will determine the protein interactive site(s) of these metals and distinguish between toxic effects on the calcium messenger system and direct actions on apical DFTR channels. Studies will be carried out in the in vitro perfused rectal gland, in primary culture monolayers of rectal gland cells, and in Xenopus oocytes expressing the DFTR chloride channel.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Center Core Grants (P30)
Project #
5P30ES003828-15
Application #
6301304
Study Section
Project Start
2000-04-01
Project End
2001-03-31
Budget Start
1998-10-01
Budget End
1999-09-30
Support Year
15
Fiscal Year
2000
Total Cost
$35,639
Indirect Cost
Name
Mount Desert Island Biological Lab
Department
Type
DUNS #
City
Salisbury Cove
State
ME
Country
United States
Zip Code
04672
Hahn, Mark E; Karchner, Sibel I; Merson, Rebeka R (2017) Diversity as Opportunity: Insights from 600 Million Years of AHR Evolution. Curr Opin Toxicol 2:58-71
Telles, Connor J; Decker, Sarah E; Motley, William W et al. (2016) Functional and molecular identification of a TASK-1 potassium channel regulating chloride secretion through CFTR channels in the shark rectal gland: implications for cystic fibrosis. Am J Physiol Cell Physiol 311:C884-C894
Forrest Jr, John N (2016) THE SHARK RECTAL GLAND MODEL: A CHAMPION OF RECEPTOR MEDIATED CHLORIDE SECRETION THROUGH CFTR. Trans Am Clin Climatol Assoc 127:162-175
Schwarz, Julia S; de Jonge, Hugo R; Forrest Jr, John N (2015) Value of Organoids from Comparative Epithelia Models. Yale J Biol Med 88:367-74
Stahl, Klaus; Stahl, Maximilian; de Jonge, Hugo R et al. (2015) ANP and CNP activate CFTR expressed in Xenopus laevis oocytes by direct activation of PKA. J Recept Signal Transduct Res 35:493-504
Kelley, Catherine A; Decker, Sarah E; Silva, Patricio et al. (2014) Gastric inhibitory peptide, serotonin, and glucagon are unexpected chloride secretagogues in the rectal gland of the skate (Leucoraja erinacea). Am J Physiol Regul Integr Comp Physiol 306:R674-80
De Jonge, Hugo R; Tilly, Ben C; Hogema, Boris M et al. (2014) cGMP inhibition of type 3 phosphodiesterase is the major mechanism by which C-type natriuretic peptide activates CFTR in the shark rectal gland. Am J Physiol Cell Physiol 306:C343-53
Barnes, D W (2012) Cell and molecular biology of the spiny dogfish Squalus acanthias and little skate Leucoraja erinacea: insights from in vitro cultured cells. J Fish Biol 80:2089-111
Miller, Hilary D; Clark, Bryan W; Hinton, David E et al. (2012) Anchoring ethinylestradiol induced gene expression changes with testicular morphology and reproductive function in the medaka. PLoS One 7:e52479
Stahl, Maximilian; Stahl, Klaus; Brubacher, Marie B et al. (2012) Divergent CFTR orthologs respond differently to the channel inhibitors CFTRinh-172, glibenclamide, and GlyH-101. Am J Physiol Cell Physiol 302:C67-76

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