The role of Kv1.2-containing potassium channels in serotonin-induced glutamate release from thalamocortical terminals in rat frontal cortex.
Serotonin 5-HT(2A) receptors have been implicated in psychiatric illness and the psychotomimetic effects of hallucinogens. In brain slices, focal stimulation of 5-HT(2A) receptors in rat prefrontal cortex results in dramatically increased glutamate release onto layer V pyramidal neurons, as measured by an increase in "spontaneous" (nonelectrically evoked) EPSCs. This glutamate release is blocked by tetrodotoxin (TTX) and is thought to involve local spiking in thalamocortical axon terminals; however, the detailed mechanism has remained unclear. Here, we investigate parallels in EPSCs induced by either serotonin or the potassium channel blockers 4-aminopyridine (4-AP) or alpha-dendrotoxin (DTX). DTX, a selective blocker of Kv1.1-, Kv1.2-, and Kv1.6-containing potassium channels, has been shown to release glutamate in cortical synaptosomes, presumably by inhibiting a subthreshold-activated, slowly inactivating potassium conductance. By comparing DTX with other potassium channel blockers, we found that the ability to induce EPSCs in cortical pyramidal neurons depends on affinity for Kv1.2 subunits. DTX-induced EPSCs are similar to 5-HT-induced EPSCs in terms of sensitivity to TTX and omega-agatoxin-IVA (a blocker of P-type calcium channels) and laminar selectivity. The involvement of thalamocortical terminals in DTX-induced EPSCs was confirmed by suppression of these EPSCs by micro-opiates and thalamic lesions. More directly, DTX-induced EPSCs substantially occlude those induced by 5-HT, suggesting a common mechanism of action. No occlusion by DTX was seen when EPSCs were induced by a nicotinic mechanism. These results indicate that blockade of Kv1.2-containing potassium channels is part of the mechanism underlying 5-HT-induced glutamate release from thalamocortical terminals.
Lambe
E K
EK
Interdepartmental Neuroscience Program and Departments of Psychiatry and Pharmacology, Yale University School of Medicine, New Haven Connecticut 06508, USA. evelyn.lambe@yale.edu
Aghajanian
G K
GK
D000818:Animals; D002121:Calcium Channel Blockers / Q000494:pharmacology; D020865:Calcium Channels, P-Type / Q000187:drug effects / Q000378:metabolism; D017115:Catheter Ablation; D004546:Elapid Venoms / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology; D005625:Frontal Lobe / Q000166:cytology / Q000378:metabolism*; D005971:Glutamates / Q000378:metabolism; D018698:Glutamic Acid / Q000378:metabolism*; D066298:In Vitro Techniques; D051663:Kv1.2 Potassium Channel; D008297:Male; D009292:Narcotic Antagonists / Q000494:pharmacology; D018408:Patch-Clamp Techniques; D026902:Potassium Channel Blockers / Q000494:pharmacology; D015221:Potassium Channels / Q000378:metabolism*; D024642:Potassium Channels, Voltage-Gated; D017729:Presynaptic Terminals / Q000378:metabolism*; D017966:Pyramidal Cells / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D017450:Receptors, Opioid, mu / Q000037:antagonists & inhibitors; D012701:Serotonin / Q000494:pharmacology*; D013779:Tetrodotoxin / Q000494:pharmacology; D013788:Thalamus / Q000166:cytology / Q000502:physiology* / Q000601:surgery
D002121:Calcium Channel Blockers; D020865:Calcium Channels, P-Type; D004546:Elapid Venoms; D018691:Excitatory Amino Acid Antagonists; D005971:Glutamates; C496972:Kcna2 protein, rat; D051663:Kv1.2 Potassium Channel; D009292:Narcotic Antagonists; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated; D017450:Receptors, Opioid, mu; D012701:Serotonin; D018698:Glutamic Acid; D013779:Tetrodotoxin; C020273:dendrotoxin