title: Inflammatory mediator-induced modulation of GABAA currents in human sensory neurons.
abstract: The purpose of the present study was to characterize the properties of A-type GABA receptor (GABAA receptor) currents in human sensory neurons. Neurons were obtained from adult organ donors. GABAA currents were recorded in isolated neurons. Both large inactivating low-affinity currents and smaller persistent high-affinity currents were present in all of the 129 neurons studied from 15 donors. The kinetics of human GABAA currents were slower than those in rat sensory neurons. GABA currents were completely blocked by bicuculline (10 μM), and persistent currents were activated by the δ-subunit-preferring agonist, 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridine-3-ol (THIP). The GABA current equilibrium potential was ∼ 20 mV more hyperpolarized than in rat neurons. Both low- and high-affinity currents were increased by inflammatory mediators but via different second messenger pathways. These results highlight potentially important species differences in the properties of ion channels present in their native environment and suggest the use of human sensory neurons may be a valuable tool to test compounds prior to use in humans.
authors.affiliation: Department of Anesthesiology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.
authors.forename: X-L
authors.initials: XL
authors.lastname: Zhang
authors.affiliation: Department of Anesthesiology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.
authors.forename: K-Y
authors.initials: KY
authors.lastname: Lee
authors.affiliation: Lilly Research Laboratories, Indianapolis, IN 46285, USA.
authors.forename: B T
authors.initials: BT
authors.lastname: Priest
authors.affiliation: Department of Anesthesiology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.
authors.forename: I
authors.initials: I
authors.lastname: Belfer
authors.affiliation: Department of Anesthesiology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA; Pittsburgh Center for Pain Research, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA. Electronic address: msg22@pitt.edu.
authors.forename: M S
authors.initials: MS
authors.lastname: Gold
mesh_terms: D000328:Adult; D005260:Female; D058785:GABA-A Receptor Agonists / Q000494:pharmacology; D005727:Ganglia, Spinal / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D018836:Inflammation Mediators / Q000494:pharmacology; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D008875:Middle Aged; D011963:Receptors, GABA-A / Q000502:physiology*; D011984:Sensory Receptor Cells / Q000187:drug effects / Q000502:physiology*; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology
chemical_list: D058785:GABA-A Receptor Agonists; D018836:Inflammation Mediators; D011963:Receptors, GABA-A; D005680:gamma-Aminobutyric Acid
keywords: dorsal root ganglion; intracellular Cl(−) concentration; patch clamp; protein kinase A; protein kinase C; tyrosine kinase