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This Article Full Text Full Text (PDF) All Versions of this Article: 289/6/R1644    most recent 00098.2005v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Web of Science (3) Citing Articles via Google Scholar Google Scholar Articles by Chernova, M. N. Articles by Alper, S. L. Search for Related Content PubMed PubMed Citation Articles by Chernova, M. N. Articles by Alper, S. L.

APPETITE, OBESITY, DIGESTION, AND METABOLISM

Apparent receptor-mediated activation of Ca²⁺-dependent conductive Cl^– transport by shark-derived polyaminosterols

¹Molecular and Vascular Medicine and Renal Units, Beth Israel Deaconess Medical Center, Department of Medicine Harvard Medical School, Boston, Massachusetts; and ²Genaera Corporation, Plymouth Meeting, Pennsylvania

Submitted 11 February 2005 ; accepted in final form 27 July 2005

The shark liver antimicrobial polyaminosterol squalamine is an angiogenesis inhibitor under clinical investigation as an anti-cancer agent and as a treatment for the choroidal neovascularization associated with macular degeneration of the retina. The related polyaminosterol MSI-1436 is an appetite suppressant that decreases systemic insulin resistance. However, the mechanisms of action of these polyaminosterols are unknown. We report effects of MSI-1436 on Xenopus oocytes consistent with the existence of a receptor for polyaminosterols. MSI-1436 activates bidirectional, trans-chloride-independent Cl^- flux in Xenopus oocytes. At least part of this DIDS-sensitive Cl^– flux is conductive, as measured using two-electrode voltage-clamp and on-cell patch-clamp techniques. MSI-1436 also elevates cytosolic Ca²⁺ concentration ([Ca²⁺]) and increases bidirectional ⁴⁵Ca²⁺ flux. Activation of Cl^– flux and elevation of cytosolic [Ca²⁺] by MSI-1436 both are accelerated by lowering bath Ca²⁺ and are not acutely inhibited by extracellular EGTA. Elevation of cytosolic [Ca²⁺] by MSI-1436 requires heparin-sensitive intracellular Ca²⁺ stores. Although injected EGTA abolishes the increased conductive Cl^– flux, that Cl^– flux is not dependent on heparin-sensitive stores. In low-bath Ca²⁺ conditions, several structurally related polyaminosterols act as strong agonists or weak agonists of conductive Cl^– flux in oocytes. Weak agonist polyaminosterols antagonize the strong agonist, MSI-1436, but upon addition of the conductive Cl^– transport inhibitor DIDS, they are converted into strong agonists. Together, these properties operationally define a polyaminosterol receptor at or near the surface of the Xenopus oocyte, provide an initial description of receptor signaling, and suggest routes toward further understanding of a novel class of appetite suppressants and angiogenesis inhibitors.

MSI-1436; calcium-dependent chloride conductance; Xenopus oocyte; 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid