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The Journal of Neuroscience, August 15, 1999, 19(16):6825-6837

Modulation of a Slowly Inactivating Potassium Current, I_D, by Metabotropic Glutamate Receptor Activation in Cultured Hippocampal Pyramidal Neurons

Rui-Lin Wu and Michael E. Barish

Division of Neurosciences, Beckman Research Institute of the City of Hope, Duarte, California 91010

I_D is a slowly inactivating 4-aminopyridine (4-AP)-sensitive potassium current of hippocampal pyramidal neurons and other CNS neurons. Although I_D exerts multifaceted influence on CNS excitability, whether I_D is subject to modulation by neurotransmitters or neurohormones has not been clear.

We report here that one prominent effect of metabotropic glutamate receptor (mGluR) activation by short (3 min) exposure to 1S,3R-1-aminocyclopentane-1,3-dicarboxylic acid (1S,3R-ACPD) (100 µM) is suppression of I_D by acceleration of its inactivation. I_D was identified as a target of mGluR-mediated modulation because inactivation of a component of outward current sensitive to 100-200 µM 4-AP was accelerated by 1S,3R-ACPD, and because 4-AP occluded any further actions of 1S,3R-ACPD. Enhancement of I_D inactivation was induced by the group I-preferring agonist RS-3,5-dihydroxyphenylglycine (3,5-DHPG) and the group II-preferring agonist 2S,2'R,3'R)-2-(2',3'dicarboxycyclopropyl)-glycine (DCG-IV), but not by the group III-preferring agonist L(+)-2-amino-4-phosphonobutyric acid (L-AP4); it was blocked by the broadly acting mGluR antagonist S--methyl-4-carboxyphenylglycine (S-MCPG). Furthermore, inactivation of I_D was enhanced by inclusion of GTPS in the internal solution and blocked by inclusion of GDPS.

Metabotropic GluR-induced suppression of I_D was manifest in three aspects of excitability previously linked to I_D by their sensitivity to 4-AP: reduction in input conductance and enhanced excitability at voltages just positive to the resting potential, reduced delay to action potential firing during depolarizing current injections, and delayed action potential repolarization. We suggest that mGluR-induced suppression of I_D could contribute to enhancement of hippocampal neuron excitability and synaptic connections.

Key words: metabotropic glutamate receptor; 4-aminopyridine; potassium current; I_D; hippocampus; pyramidal neuron; regulation of excitability

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Copyright © 1999 Society for Neuroscience  0270-6474/99/19166825-13$05.00/0

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