title: Synaptic-type α1β2γ2L GABAA receptors produce large persistent currents in the presence of ambient GABA and anesthetic drugs.
abstract: Synaptic GABAA receptors respond to synaptically released GABA and are considered to be unaffected by the low levels of ambient transmitter in the brain. We show that synaptic-type α1β2γ2L GABAA receptors expressed in HEK293 cells respond with large steady-state currents to combinations of a low concentration (0.5 μM) of GABA and clinically used GABAergic modulators propofol, etomidate, or pentobarbital or the steroid alphaxalone. At a maximally effective concentration of modulator, the current levels at the end of 2-minute applications of drug combinations were >10% of the peak response to saturating GABA. In the absence of modulators, 0.5 μM GABA generated a steady-state response of 1% of the peak response to saturating GABA. The concentration-response curves for enhancement of steady-state currents by propofol, etomidate, pentobarbital, or alphaxalone were at similar or lower drug concentrations compared with concentration-response relationships for enhancement of peak responses. We propose that modulation of tonically activated synaptic-type GABAA receptors contributes to the clinical actions of sedative drugs.
authors: Department of Anesthesiology (P.L., G.A.) and the Taylor Family Institute for Innovative Psychiatric Research (G.A.), Washington University School of Medicine, St. Louis, Missouri.
authors: Ping
authors: P
authors: Li
authors: Department of Anesthesiology (P.L., G.A.) and the Taylor Family Institute for Innovative Psychiatric Research (G.A.), Washington University School of Medicine, St. Louis, Missouri akk@morpheus.wustl.edu.
authors: Gustav
authors: G
authors: Akk
mesh_terms: D000777:Anesthetics / Q000494:pharmacology*; D000818:Animals; D002460:Cell Line; D023902:Chromosome Pairing / Q000187:drug effects*; D005045:Etomidate / Q000494:pharmacology; D057809:HEK293 Cells; D006801:Humans; D010424:Pentobarbital / Q000494:pharmacology; D011277:Pregnanediones / Q000494:pharmacology; D015742:Propofol / Q000494:pharmacology; D051381:Rats; D011963:Receptors, GABA-A / Q000378:metabolism*; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology*
chemical_list: D000777:Anesthetics; D011277:Pregnanediones; D011963:Receptors, GABA-A; D005680:gamma-Aminobutyric Acid; C006477:alphaxalone; D010424:Pentobarbital; D015742:Propofol; D005045:Etomidate