Modulation of a slowly inactivating potassium current, ID, by metabotropic glutamate receptor activation in cultured hippocampal pyramidal neurons

I, 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 mu M) 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 mu M 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-APL); it was blocked by the broadly acting mGluR antagonist S-alpha-methyl-4-carboxyphenylglycine (S-MCPG). Furthermore, inactivation of I-D was enhanced by inclusion of GTP gamma S in the internal solution and blocked by inclusion of GDP beta S. 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.