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

I, is a slowly inactivating 4-aminopyridine (4-AP)-sensitive potassium curr ent of hippocampal pyramidal neurons and other CNS neurons. Although I-D ex erts 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 acce leration of its inactivation. I-D was identified as a target of mGluR-media ted modulation because inactivation of a component of outward current sensi tive to 100-200 mu M 4-AP was accelerated by 1S,3R-ACPD, and because 4-AP o ccluded 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'-dicarb oxycyclopropyl)-glycine (DCG-IV), but not by the group III-preferring agoni st L(+)-2-amino-4-phosphonobutyric acid (L-APL); it was blocked by the broa dly 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: redu ction in input conductance and enhanced excitability at voltages just posit ive to the resting potential, reduced delay to action potential firing duri ng depolarizing current injections, and delayed action potential repolariza tion. We suggest that mGluR-induced suppression of I-D could contribute to enhancement of hippocampal neuron excitability and synaptic connections.