title: Comparison between drug-induced and K⁺-induced changes in molar acid extrusion fluxes (JH⁺) and in energy consumption rates in astrocytes.
abstract: Neuronal excitation leads to an increase of the extracellular K(+) concentration ([K(+)]o) in brain. This increase has at least two energy-consuming consequences: (1) a depolarization-mediated change in intracellular pH (pHi) in astrocytes due to depolarization-mediated increased activity of the acid-extruding Na(+)/bicarbonate transporter NBCe1 (driven by secondary active transport, supported by ion gradients established by the Na(+), K(+)-ATPase); and (2) activation of cellular reuptake of K(+) mediated by the Na(+), K(+)-ATPase in both neurons and astrocytes. Astrocytic, but not neuronal increase in NBCe1 activity and pHi is also seen after chronic treatment with either of the two anti-bipolar drugs carbamazepine or valproic acid. The third 'classical' anti-bipolar drug, 'lithium' increases astrocytic pHi by a different mechanism (stimulation of the acid extruding Na(+)/H(+) exchanger NHE1). The acid extruder fluxes, which depend upon the change in pHi per time unit (ΔpHi/Δt) and intracellular buffering power, have not been established in most of these situations. Therefore their stimulatory effects on energy metabolism has not been quantitated. This has been done in the present study in cultured mouse astrocytes. pHi was determined using the fluorescent pH-sensitive indicator BCECF-AM and an Olympus IX71 live cell imaging fluorescence microscope. Molar acid extrusion fluxes (indicating transporter activity) were determined as pHi changes/min during recovery after acid-loading with NH3/NH4 (+), NBCe1 mRNA and protein expression in the cultured cells by, respectively RT-PCR and Western blotting. Drug-induced up-regulation of acid extrusion flux was slow and less than physiologically seen after increase in K(+) concentration. Energetically, K(+) uptake is much costlier than NBCe1 activity.
authors.affiliation: Department of Clinical Pharmacology and Institute of Pathology and Pathophysiology, China Medical University, No. 92 Beier Road, Heping District, Shenyang, People's Republic of China.
authors.forename: Dan
authors.initials: D
authors.lastname: Song
authors.forename: Yi
authors.initials: Y
authors.lastname: Man
authors.forename: Baoman
authors.initials: B
authors.lastname: Li
authors.forename: Junnan
authors.initials: J
authors.lastname: Xu
authors.forename: Leif
authors.initials: L
authors.lastname: Hertz
authors.forename: Liang
authors.initials: L
authors.lastname: Peng
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism; D002220:Carbamazepine / Q000494:pharmacology; D006863:Hydrogen-Ion Concentration / Q000187:drug effects; D051379:Mice; D011188:Potassium / Q000494:pharmacology*; D027982:Sodium-Bicarbonate Symporters / Q000378:metabolism*; D014635:Valproic Acid / Q000494:pharmacology
chemical_list: C498899:Slc4a4 protein, mouse; D027982:Sodium-Bicarbonate Symporters; D002220:Carbamazepine; D014635:Valproic Acid; D011188:Potassium
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