title: T-type calcium channels contribute to calcium disturbances in brain during hyponatremia.
abstract: Disturbance of calcium homeostasis is implicated in the normal process of aging and brain pathology prevalent in the elderly such as Alzheimer's, Parkinson's, and amyotrophic lateral sclerosis. Previous studies demonstrated that applying a hyponatremic iso-osmotic (low-NaCl) artificial cerebrospinal fluid (ACSF) to rodent hippocampus causes extracellular calcium to rapidly decrease. Restoring normonatremia after low-NaCl treatment causes a rapid increase in extracellular calcium that overshoots baseline. This study examined the amplitude, timing, and mechanism of these surprising calcium changes. We also tested whether hyponatremia increased calcium entry into brain cells or calcium binding to chondroitin sulfate (CS), a negatively charged constituent of the extracellular matrix (ECM) that may be occupied by sodium during normonatremia. We report three major findings. First we show that CS does not contribute to extracellular calcium changes during low-NaCl treatments. Second, we show that the time to minimum extracellular calcium during low-NaCl treatment is significantly shorter than the time to maximum extracellular calcium in recovery from low-NaCl treatment. Third, we show that the decrease in extracellular calcium observed during hyponatremia is attenuated by ML 218, a highly selective T-type calcium channel blocker. Together these data suggest that calcium rapidly enters cells at the onset of low-NaCl treatment and is extruded from cells when normonatremia is restored. Calcium binding to CS does not significantly contribute to calcium changes in brain during hyponatremia. Differences in timing suggest that extracellular calcium changes during and in recovery from hyponatremia occur by distinct mechanisms or by a multistep process. Finally, partial block of extracellular calcium influx by ML 218 suggests that T-type channels are involved in calcium entering cells during hyponatremia. Given the high prevalence of hyponatremia among elderly patients and the growing understanding of calcium's role in multiple neurologic pathologies, this study promotes a novel approach for studying and potentially preventing the effects of hyponatremia on calcium dysregulation in brain tissue.
authors.affiliation: College of Medicine, SUNY Downstate Medical Center, 450 Clarkson Avenue, Brooklyn, NY 11203, USA. Electronic address: john.odackal@downstate.edu.
authors.forename: John
authors.initials: J
authors.lastname: Odackal
authors.affiliation: Department of Cell Biology, SUNY Downstate Medical Center, 450 Clarkson Avenue, Brooklyn, NY 11203, USA; Neural and Behavioral Science Graduate Program, SUNY Downstate Medical Center, 450 Clarkson Avenue, Brooklyn, NY 11203, USA.
authors.forename: Ang D
authors.initials: AD
authors.lastname: Sherpa
authors.affiliation: Department of Cell Biology, SUNY Downstate Medical Center, 450 Clarkson Avenue, Brooklyn, NY 11203, USA.
authors.forename: Nisha
authors.initials: N
authors.lastname: Patel
authors.affiliation: College of Medicine, SUNY Downstate Medical Center, 450 Clarkson Avenue, Brooklyn, NY 11203, USA; Department of Cell Biology, SUNY Downstate Medical Center, 450 Clarkson Avenue, Brooklyn, NY 11203, USA; School of Graduate Studies, SUNY Downstate Medical Center, 450 Clarkson Avenue, Brooklyn, NY 11203, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Colbourn
authors.affiliation: Department of Cell Biology, SUNY Downstate Medical Center, 450 Clarkson Avenue, Brooklyn, NY 11203, USA; The Robert Furchgott Center for Neural and Behavioral Science, SUNY Downstate Medical Center, 450 Clarkson Avenue, Brooklyn, NY 11203, USA.
authors.forename: Sabina
authors.initials: S
authors.lastname: Hrabetova
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism*; D002121:Calcium Channel Blockers / Q000494:pharmacology; D020747:Calcium Channels, T-Type / Q000378:metabolism*; D019765:Chondroitin ABC Lyase / Q000494:pharmacology; D004195:Disease Models, Animal; D005110:Extracellular Space / Q000378:metabolism; D007010:Hyponatremia / Q000473:pathology*; D066298:In Vitro Techniques; D017736:Ion-Selective Electrodes; D051379:Mice; D008810:Mice, Inbred C57BL; D009994:Osmolar Concentration
chemical_list: D002121:Calcium Channel Blockers; D020747:Calcium Channels, T-Type; D019765:Chondroitin ABC Lyase; D002118:Calcium
keywords: Aging; Calcium homeostasis; Chondroitin sulfate; Elderly patients; Extracellular matrix; Hippocampus; Hyponatremia; Neurodegeneration; T-type calcium channels