ORIGINAL PAPER Voltage-gated Calcium Channels Provide an Alternate Route for Iron Uptake in Neuronal Cell Cultures Julie A. Gaasch Æ Werner J. Geldenhuys Æ Paul R. Lockman Æ David D. Allen Æ Cornelis J. Van der Schyf Accepted: 8 February 2007 / Published online: 3 April 2007 Ó Springer Science+Business Media, LLC 2007 Abstract Recent studies suggest that iron enters cardiomyocytes via the L-type voltage-gated calcium channel (VGCC). The neuronal VGCC may also pro- vide iron entry. As with calcium, extraneous iron is associated with the pathology and progression of neurodegenerative diseases such as Parkinson’s and Alzheimer’s disease. VGCCs, ubiquitously expressed, may be an important route of excessive entry for both iron and calcium, contributing to cell toxicity or death. We evaluated the uptake of 45 Ca 2+ and 55 Fe 2+ into NGF-treated rat PC12, and murine N-2a cells. Iron not only competed with calcium for entry into these cells, but iron uptake (similar to calcium uptake) was inhibited by nimodipine, a specific L-type VGCC blocker, and enhanced by FPL 64176, an L-VGCC activator, in a dose-dependent manner. Taken together, these data suggest that voltage-gated calcium channels are an alternate route for iron entry into neuronal cells under conditions that promote cellular iron overload toxicity. Keywords Alzheimer’s disease Á Iron-overload toxicity Á Neurodegeneration Á Nimodipine Á Parkinson’s disease Á Voltage-gated calcium channels Abbreviations AD Alzheimer’s disease PD Parkinson’s disease VGCC Voltage-gated calcium channel ROS Reactive oxygen species NGF Nerve growth factor ICH Intracerebral hemorrhage SAH Subarachnoid hemorrhage Tf Transferrin CSF Cerebrospinal fluid IF Interstitial fluid Lf Lactoferrin DMT-1 Divalent metal transporter-1 Iron plays a pivotal role in physiological brain function as an essential component of cytochromes, iron-sulfur complexes, hemoglobin, and as a cofactor for neuro- transmitter, lipid, and DNA synthesis [1], however, the presence of excess iron can be neurotoxic. Iron accu- mulation is observed in a number of neurodegenerative disorders such as Neurodegeneration with Brain Iron Accumulation Type 1 (NBIA1) and Huntington dis- ease [1]. More recently, compelling data have sug- gested that iron accumulation is associated with the development and progression of Parkinson’s (PD) [2] and Alzheimer’s disease (AD) [3]. Excessive free iron may also be a source of free radical damage to neu- ronal cells in hemorrhagic stroke [4]. A primary Special issue dedicated to Dr. Moussa Youdim. J. A. Gaasch Á P. R. Lockman Department of Pharmaceutical Sciences, Texas Tech University Health Sciences Center, School of Pharmacy, Amarillo, Texas 79106, USA W. J. Geldenhuys Á D. D. Allen Á C. J. Van der Schyf (&) Department of Pharmaceutical Sciences, Northeastern Ohio Universities College of Pharmacy, 4209 State Route 44, Rootstown, OH 44272-9698, USA e-mail: cvanders@neoucom.edu C. J. Van der Schyf Department of Pharmaceutical Chemistry, North-West University, Potchefstroom 2520, South Africa 123 Neurochem Res (2007) 32:1686–1693 DOI 10.1007/s11064-007-9313-1