Neurotransmitter activation of inwardly rectifying potassium current in dissociated hippocampal CA3 neurons: interactions among multiple receptors.
We characterized potassium current activated by G-protein-coupled receptors in acutely dissociated hippocampal CA3 neurons. Agonists for serotonin, adenosine, and somatostatin receptors reliably activated a potassium-selective conductance that was inwardly rectifying and that was blocked by 1 mM external Ba2+. The conductance had identical properties to that activated by GABAB receptors in the same cells. In one-half of the CA3 neurons that were tested, the metabotropic glutamate agonist 1S,3R-ACPD also activated inwardly rectifying Ba2+-sensitive potassium current. Activation of the current by serotonin and adenosine agonists occurred with a time constant of 200-700 msec after a lag of 50-100 msec; on removal of agonist the current deactivated with a time constant of 1-2 sec after a lag of 200-400 msec. These kinetics are similar to GABAB-activated current and consistent with a direct action of G-protein on the channels. For somatostatin, both activation and deactivation were approximately fourfold slower, probably limited by agonist binding and unbinding. The half-maximally effective agonist concentrations were approximately 75 nM for somatostatin, approximately 100 nM for serotonin, and approximately 400 nM for 2-chloroadenosine. Dose-response relationships had Hill coefficients of 1.2-1.9, suggesting cooperativity in the receptor-to-channel coupling mechanism. At saturating concentrations of agonists, the combined application of baclofen and either somatostatin, serotonin, or 2-chloroadenosine produced effects that were subadditive and often completely occlusive. However, at subsaturating concentrations the effects of baclofen and 2-chloroadenosine were supra-additive. Thus, low levels of different transmitters can act synergistically in activating inwardly rectifying potassium current.
Department of Neurobiology, Harvard Medical School, Boston, Massachusetts 02115, USA.
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D015762:2-Chloroadenosine / Q000494:pharmacology; D000818:Animals; D001418:Baclofen / Q000494:pharmacology; D001464:Barium / Q000494:pharmacology; D002478:Cells, Cultured; D003515:Cycloleucine / Q000031:analogs & derivatives / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004594:Electrophysiology; D018755:GABA Agonists / Q000494:pharmacology; D006624:Hippocampus / Q000737:chemistry / Q000166:cytology; D008564:Membrane Potentials / Q000187:drug effects; D018696:Neuroprotective Agents / Q000494:pharmacology; D015221:Potassium Channels / Q000819:agonists / Q000502:physiology*; D024661:Potassium Channels, Inwardly Rectifying; D017966:Pyramidal Cells / Q000737:chemistry* / Q000166:cytology / Q000187:drug effects; D051381:Rats; D020318:Rats, Long-Evans; D018080:Receptors, GABA-B / Q000502:physiology; D018094:Receptors, Metabotropic Glutamate / Q000502:physiology; D012701:Serotonin / Q000494:pharmacology*; D013004:Somatostatin / Q000494:pharmacology*
D018755:GABA Agonists; D018696:Neuroprotective Agents; D015221:Potassium Channels; D024661:Potassium Channels, Inwardly Rectifying; D018080:Receptors, GABA-B; D018094:Receptors, Metabotropic Glutamate; D003515:Cycloleucine; C036361:1-amino-1,3-dicarboxycyclopentane; D015762:2-Chloroadenosine; D001464:Barium; D012701:Serotonin; D013004:Somatostatin; D001418:Baclofen