ABSTRACT
Maitotoxin (MTX), produced by the marine dinofl agellate Gambierdiscus toxicus, is arguably the most potent non-peptide toxin known with reported LD50 values in mice ranging from 80-170 ng/kg (Takahashi et al. 1982, Holmes and Lewis 1994). At sub-lethal concentrations MTX causes a plethora of biological effects at the cell and tissue level including contraction of skeletal, cardiac and smooth muscles, release of neurotransmitters and hormones, platelet aggregation, phosphatidylinositol hydrolysis, arachidonic acid release, activation of calpain, and protein tyrosine phosphorylation. Although one might conclude from this extensive list that MTX has numerous cellular targets, the singular defi ning event common to all MTX-induced cytotoxicities is a rapid, and in many cases, profound increase in the cytosolic free Ca2+ concentration ([Ca2+]i). As a result, MTX causes specific and predictable secondary pharmacological effects in virtually all cells and tissues. Following the advent of fl uorescence Ca2+ indicators, the effect of MTX on [Ca2+]i was examined in a variety of cell
Rammelkamp Center for Education and Research, MetroHealth Medical Center; and Department of Physiology and Biophysics, Case Western Reserve University School of Medicine. Email: wschilling@metrohealth.org
types. A rise in [Ca2+]i in response to MTX has been observed in essentially all cells examined to date including bovine aortic endothelial cells (BAECs) (Estacion and Schilling 2001, Wisnoskey et al. 2004), mouse pancreatic β-cells (Worley III et al. 1994), human skin fi broblasts (Schilling et al. 1999a), rat insulinoma cells (Soergel et al. 1992), human SH-SY5Y neuroblastoma cells (Wang et al. 1996), rat PC-12 cells (Choi et al. 1990), rat C6 glioma cells (Murata et al. 1992), HL-60 cells (Musgrave et al. 1994), human embryonic kidney (HEK) cells (Schilling et al. 1999b), THP-1 monocytes (Schilling et al. 1999b), BAC1 macrophages (Verhoef et al. 2004), and BW5147.3 lymphoma cells (Schilling et al. 1999b) to name just a few. MTX-induced responses are also observed in various species including sea urchin eggs (Pesando et al. 1991), Xenopus oocytes (Bielfeld-Ackermann et al. 1998), crayfi sh neurons (Nishio et al. 1993), and insect myocytes (Miyamoto et al. 1984). Thus, the molecular target of MTX must be widely expressed and highly conserved throughout evolution. The ultimate consequence of MTX challenge at the cellular level is Ca2+ overload-induced necrotic cell death. In this chapter I will 1) briefl y review the importance of cellular Ca2+ homeostasis to cell signaling and survival, 2) describe the changes in plasmalemmal permeability that occur in response to MTX that ultimately lead to cell lysis, and 3) discuss recent evidence implicating the plasmalemmal Ca2+ ATPase (PMCA) pump as the molecular target of MTX action.
