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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