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 here 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 by two-electrode voltage clamp and on-cell patch clamp techniques. MSI-1436 also elevates cytosolic [Ca²⁺] and increases bidirectional ⁴⁵Ca²⁺ flux. Activation of Cl^- flux and elevation of cytosolic [Ca²⁺] by MSI-1436 are both 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, 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 towards further understanding of a novel class of appetite suppressants and angiogenesis inhibitors.