Abstract
Copper plays a key role in aerobic cell physiology mainly related to mitochondrial metabolism. This element is also present at higher than basal levels in some central nuclei and indeed, current evidence support copper’s role as a neuromodulator in the central nervous system. More recent data indicate that copper may also affect peripheral neuronal activity, but so far, there are not detailed descriptions of what peripheral neuronal characteristics are targeted by copper. Here, we studied the effect of physiological concentration of CuCl2 (μM range) on the activity of peripheral neurons using a preparation of nodose ganglion in vitro. By mean of conventional intracellular recordings passive and active electrical membrane properties were studied. Extracellular copper modified (in a redox-independent manner) the resting membrane potential and the input resistance of the nodose ganglion neurons, increasing the excitability in most of the tested neurons. These results suggest that Cu2+ modulates the activity of nodose ganglion neurons and support nodose ganglion in vitro preparation as a simple model to study the subcellular mechanisms involved in the Cu2+ effects on neuron electrical properties.
Similar content being viewed by others
References
Aedo F, Delgado R, Wolff D, Vergara C (2007) Copper and zinc as modulators of neuronal excitability in a physiologically significant concentration range. Neurochem Int 50:591–600
Aldunate R, Minniti AN, Rebolledo D, Inestrosa NC (2012) Synaptic defects associated with s-inclusion body myositis are prevented by copper. Biometals 4:815–824
Alissa EM, Bahijri SM, Lamb DJ, Ferns GAA (2004) The effects of coadministration of dietary copper and zinc supplements on atherosclerosis, antioxidant enzymes and indices of lipid peroxidation in the cholesterol-fed rabbit. Int J Exp Path 85:265–275
Belmonte C, Gallego R (1983) Membrane properties of cat sensory neurones with chemoreceptor and baroreceptor endings. J Physiol 342:603–614
Castelli L, Tanzi F, Taglietti V, Magistretti J (2003) Cu2+, Co2+, and Mn2+ modify the gating kinetics of high-voltage-activated Ca2+ channels in rat palaeocortical neurons. J Membr Biol 195:121–136
Chen J, Myerburg MM, Passero CJ, Winarski KL, Sheng S (2011) External Cu2+ inhibits human epithelial Na+ channels by binding at a subunit interface of extracellular domains. J Biol Chem 286:27436–27446
Colvin RA, Fontaine CP, Laskowski M, Thomas D (2003) Zn2+ transporters and Zn2+ homeostasis in neurons. Eur J Pharmacol 479:171–185
Copello J, Heming TA, Segal Y, Reuss L (1993) cAMP-activated apical membrane chloride channels in Necturus gallbladder epithelium. Conductance, selectivity, and block. J Gen Physiol 102:177–199
de Bie P, Muller P, Wijmenga C, Klomp LW (2007) Molecular pathogenesis of Wilson and Menkes disease: correlation of mutations with molecular defects and disease phenotypes. J Med Genet 44:673–688
Degnan KJ (1985) The role of K+ and Cl− conductances in chloride secretion by the opercular epithelium. J Exp Zool 236:19–25
Delgado R, Vergara C, Wolf D (2006) Divalent cations as modulators of neuronal excitability: emphasis on copper and zinc. Biol Res 39:173–182
Eskici G, Axelsen PH (2012) Copper and oxidative stress in the pathogenesis of Alzheimer’s disease. Biochemistry 32:6289–6311
Gaier ED, Eipper BA, Mains RE (2013) Copper signaling in the mammalian nervous system: synaptic effects. J Neurosci Res 91:2–19
Harned HS, Nuttall RL (1947) The diffusion coefficient of potassium chloride in dilute aqueous solution. J Am Chem Soc 69:736–740
Horning MS, Trombley P (2001) Zinc and copper influence excitability of rat olfactory bulb neurons by multiple mechanisms. J Neurophysiol 86:1652–1660
Huidobro-Toro JP, Lorca RA, Coddou C (2008) Trace metals in the brain: allosteric modulators of ligand-gated receptor channels, the case of ATP-gated P2X receptors. Eur Biophys J 3:301–314
Kardos J, Kovács I, Hajós F, Kálmán M, Simonyi M (1989) Nerve endings from rat brain tissue release copper upon depolarization. A possible role in regulating neuronal excitability. Neurosci Lett 103:139–144
Kodama H, Fujisawa C, Bhadhprasit W (2011) Pathology, clinical features and treatments of congenital copper metabolic disorders—focus on neurologic aspects. Brain Dev 33:243–251
Li C, Peoples RW, Weight FF (1996) Cu2+ potently enhances ATP-activated current in rat nodose ganglion neurons. Neurosci Lett 219:45–48
Lobo V, Ribeiro A, Verissimo L (1998) Diffusion coefficients in aqueous solutions of potassium chloride at high and low concentrations. J Mol Liq 78:139–149
Lu L, Wang C, Gao X, Xu P, Wang J, Wang Q, Cheng J, Xiao H (2009) Effects of copper on T-type Ca2+ channels in mouse spermatogenic cells. J Membr Biol 227:87–94
Mathie A, Sutton GL, Clarke CE, Veale EL (2006) Zinc and copper: pharmacological probes and endogenous modulators of neuronal excitability. Pharmacol Ther 111:567–583
Maureira CH, Delgado R, Wolff D, Vergara C (2006) Submicromolar concentrations of Cu2+ and Zn2+ upregulate electrical activity of CA1 neurons in rat hippocampal brain slices. Program No. 432.9. 2006 Neuroscience Meeting Planner. Society for Neuroscience, Atlanta. Online
Merner ND, Dion PA, Rouleau GA (2011) Recent advances in the genetics of distal hereditary motor neuropathy give insight to a disease mechanism involving copper homeostasis that may extend to other motor neuron disorders. Clin Genet 79:23–34
Niu X, Liu G, Wu RS, Chudasama N, Zakharov SI, Karlin A, Marx SO (2013) Orientations and proximities of the extracellular ends of transmembrane helices S0 and S4 in open and closed BK potassium channels. PLoS ONE 8:e58335. doi:10.1371/journal.pone.0058335
Osiewacz HD, Borghouts C (2000) Cellular copper homeostasis, mitochondrial DNA instabilities, and lifespan control in the filamentous fungus Podospora anserine. Exp Gerontol 35:677–686
Quinta-Ferreira ME, Matias CM (2004) Hippocampal mossy fiber calcium transients are maintained during long-term potentiation and are inhibited by endogenous zinc. Brain Res 1004:52–60
Rebolledo DL, Aldunate R, Kohn R, Neira I, Minniti AN, Inestrosa NC (2011) Copper reduces Aβ oligomeric species and ameliorates neuromuscular synaptic defects in a C. elegans model of inclusion body myositis. J Neurosci 31:10149–10158
Reddy BS, Pleasants JR, Zimmerman DR, Wostmann BS (1965) Iron and copper utilization in rabbits as affected by diet and germfree status. J Nutrition 87:189–196
Reyes H, Báez ME, González MC, Hernández I, Palma J, Ribalta J, Sandoval L, Zapata R (2000) Selenium, zinc and copper plasma levels in intrahepatic cholestasis of pregnancy, in normal pregnancies and in healthy individuals, in Chile. J Hepatol 32:542–549
Ribeiro ACF, Esteso MA, Lobo VMM, Valente AJM, Simoes SMN, Sobral AJFN, Burrows HD (2005) Diffusion coefficients of copper chloride in aqueous solutions at 298.15 K and 310.15 K. J Chem Eng Data 50:1986–1990
Roos PM, Vesterberg O, Syversen T, Flaten TP, Nordberg M (2013) Metal concentrations in cerebrospinal fluid and blood plasma from patients with amyotrophic lateral sclerosis. Biol Trace Elem Res 2:159–170
Rossi L, Lombardo MF, Ciriolo MR, Rotilio G (2004) Mitochondrial dysfunction in neurodegenerative diseases associated with copper imbalance. Neurochem Res 29:493–504
Salazar-Weber NL, Smith JP (2011) Copper inhibits NMDA receptor-independent LTP and modulates the paired-pulse ratio after LTP in mouse hippocampal slices. Int J Alzheimers Dis 2011:864753
Sato M, Ohtomo K, Daimon T, Sugiyama T, Iijima K (1994) Localization of copper to afferent terminals in rat locus ceruleus, in contrast to mitochondrial copper in cerebellum. J Histochem Cytochem 42:1585–1591
SkulskiiI A, Lapin AV (1992) Highly selective blockade of the frog skin sodium channels by monovalent copper cations. Biochim Biophys Acta 1112:27–28
Tarohda T, Yamamoto M, Amamo R (2004) Regional distribution of manganese, iron, copper, and zinc in the rat brain during development. Anal Bioanal Chem 380:240–246
Trombley PQ, Shepherd GM (1996) Differential modulation by zinc and copper of amino acid receptors from rat olfactory bulb neurons. J Neurophysiol 76:2536–2546
Trombley PQ, Horning MS, Blakemore LJ (2000) Interactions between carnosine and zinc and copper: implications for neuromodulation and neuroprotection. Biochemistry (Mosc) 65:807–816
Weiser T, Wienrich M (1996) The effects of copper ions on glutamate receptors in cultured rat cortical neurons. Brain Res 742:211–218
Acknowledgments
Financial support by Fondo Nacional de Desarrollo Científico y Tecnológico (FONDECYT, Chile), project 1080670 (to CV).
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Ortiz, F.C., Vergara, C. & Alcayaga, J. Micromolar copper modifies electrical properties and spontaneous discharges of nodose ganglion neurons in vitro. Biometals 27, 45–52 (2014). https://doi.org/10.1007/s10534-013-9685-4
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10534-013-9685-4