title: Group I mGluRs evoke K-ATP current by intracellular Ca2+ mobilization in rat subthalamus neurons.
abstract: We reported previously that Ca(2+) influx through N-methly-d-aspartate-gated channels evokes ATP-sensitive K(+) (K-ATP) currents in rat subthalamic nucleus (STN) neurons. By using whole-cell patch clamp recordings in brain slices, we investigated the ability of (RS)-3,5-dihydroxyphenylglycine (DHPG), a group I metabotropic glutamate receptor (mGluR) agonist, to evoke K-ATP currents. DHPG (20 µM) evoked outward current at -70 mV and was associated with a positive slope conductance of 2.7 nS. The sulfonylurea agent tolbutamide (100 µM) converted the positive slope to negative slope conductance, indicating mediation by K-ATP channels (ATP-sensitive K+ channels). Currents evoked by DHPG were significantly reduced by a combination of mGluR1 and mGluR5 negative allosteric modulators. DHPG-evoked outward current was blocked by cyclopiazonic acid and thapsigargin and mimicked by caffeine, suggesting mediation by release of intracellular Ca(2+). DHPG outward current was also blocked by ryanodine and 2-aminoethoxydiphenylborane, suggesting mediation by ryanodine- and inositol 1,4,5-triphosphate-sensitive Ca(2+) release. The nitric oxide synthase inhibitor N(G)-nitro-l-arginine methyl ester and inhibitors of protein kinase G activity also suppressed DHPG-induced outward current. Voltage recordings showed that tolbutamide prolonged depolarizing plateau potentials and increased the spontaneous firing rate of STN neurons recorded in the presence of DHPG. These results show that group I mGluR stimulation generates K-ATP current by a nitric oxide- and protein kinase G-dependent process that is mediated by release of Ca(2+) from intracellular stores. Because burst firing is linked to symptoms of Parkinson's disease, we suggest that K-ATP channels might provide a physiologically important inhibitory influence on STN neuronal activity.
authors: Department of Neurology, Oregon Health & Science University, Portland, Oregon, USA.
authors: Ke-Zhong
authors: KZ
authors: Shen
authors: Steven W
authors: SW
authors: Johnson
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism*; D018698:Glutamic Acid / Q000378:metabolism; D005998:Glycine / Q000031:analogs & derivatives* / Q000494:pharmacology; D066298:In Vitro Techniques; D015640:Ion Channel Gating / Q000187:drug effects; D054086:KATP Channels / Q000378:metabolism*; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects*; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D018408:Patch-Clamp Techniques; D051381:Rats; D017207:Rats, Sprague-Dawley; D018094:Receptors, Metabotropic Glutamate / Q000819:agonists*; D012118:Resorcinols / Q000494:pharmacology*; D020531:Subthalamic Nucleus / Q000187:drug effects* / Q000378:metabolism
chemical_list: D054086:KATP Channels; D018094:Receptors, Metabotropic Glutamate; D012118:Resorcinols; C104077:metabotropic glutamate receptor type 1; D018698:Glutamic Acid; C079215:3,5-dihydroxyphenylglycine; D002118:Calcium; D005998:Glycine