Reduction of resting K+ current by metabotropic glutamate and muscarinic receptors in rat CA3 cells: mediation by G‐proteins.

Abstract

1. Effects of 1S,3R-1-aminocyclopentane-1,3-dicarboxylate (1S,3R-ACPD) acting at metabotropic glutamate receptors (mGluRs), and methacholine (MCh), acting at cholinergic muscarinic receptors, were investigated in CA3 neurones in hippocampal slice cultures using the patch-clamp technique.2. Both 1S,3R-ACPD (10 ,UM) and MCh (0 5 ,UM) activated an inward current associated with a decrease in membrane conductance. The current was observed when the slow calciumdependent after-hyperpolarizing current (IAHP) and the voltage-dependent current (IM)were not activated, reversed close to the reversal potential for K+ (EjK) (E = -92-8+ 10-7 and -89-2 + 8-6 mV for lS,3R-ACPD and MCh, respectively), varied linearly with membrane potential, and thus corresponds to a leak K+ current. 3. The decrease in K+ conductance elicited with 1S,3R-ACPD (50 /SM) was substantially reduced (> 70 %) with bath application of (RS)-a-methyl-4-carboxyphenylglycine (MCPG, 1 mM), a selective mGluR antagonist and was not mimicked by the enantiomer 1R,3S-ACPD (100 /1M). 4. The effects of lS,3R-ACPD and MCh were mediated by activation of G-proteins since no inward current could be elicited in GDP/?S-loaded cells (500 /uM). When cells were dialysed with GTP (100,UM) or GTPyS (250,UM), however, the amplitude of the current was significantly enhanced. 5. These findings provide evidence that G-proteins couple the activation of mGluRs and muscarinic receptors to a decrease in leak K+ conductance.Activation of metabotropic glutamate receptors (mGluRs) and muscarinic cholinergic receptors in the CNS initiates a variety of intracellular processes, such as modulation of second messenger levels and ion channel activity, which are thought to be important in synaptic plasticity and regulation of neuronal function (Nicoll, Malenka & Kauer, 1990;Schoepp & Conn, 1993 METHODSExperiments were performed using organotypic hippocampal slice cultures prepared as previously described (Giihwiler, 1981

Distinct Functional Roles of the Metabotropic Glutamate Receptors 1 and 5 in the Rat Globus Pallidus

“…For instance, in hippocampal area CA3, DHPG depolarizes neurons by inhibition of a leak potassium conductance (Guerineau et al, 1994) or by an increase in a nonspecific cationic conductance (Guerineau et al, 1995). Reduction in input resistance after stimulation with DHPG in type II GP neurons is consistent with an increase in conductance downstream of group I activation.…”

“…Such an I-V relationship could indeed be explained by a mixed effect of DHPG. Group I mGluR activation could cause both a decrease of potassium outward currents (Charpak et al, 1990;Guerineau et al, 1994), which theoretically reverse at Ϫ95 mV, and an increase of a nonspecific cationic current (Crepel et al, 1994;Guerineau et al, 1995), Figure 3. Activation of mGluR1 depolarizes type I GP neurons.…”

Functional Specificity of Gαqand Gα11in the Cholinergic and Glutamatergic Modulation of Potassium Currents and Excitability in Hippocampal Neurons

“…Beside modulating sI AHP , muscarinic and mGluR agonists induce a depolarization of the membrane potential in CA1 neurons. The underlying current has been ascribed to the inhibition of at least two types of K ϩ currents: the voltage-dependent M current (Brown and Adams, 1980;Halliwell and Adams, 1982;McCormick and Williamson, 1989) and a voltage-independent leak current (Madison et al, 1987;Guerineau et al, 1994). More recently, a cation nonselective current has been proposed to be mainly responsible for the depolarization generated by muscarinic and mGluR agonists in cortical and hippocampal neurons (Crepel et al, 1994;Greene et al, 1994;Guerineau et al, 1995;HajDahmane andAndrade, 1997, 1999).…”

“…Acetylcholine and glutamate, beside mediating fast excitatory synaptic transmission in the CNS, modulate neuronal metabolic responses by acting on metabotropic receptors (muscarinic and metabotropic glutamate receptors, mGluRs). Previous studies have focussed on the molecular and cellular mechanisms by which muscarinic and mGluR agonists regulate membrane excitability in central and peripheral neurons and have revealed their effects on several ionic currents, such as the following: (1) the M current (I M ), a voltage-dependent K ϩ current (Brown and Adams, 1980;Halliwell and Adams, 1982); (2) a voltage-independent "leak" K ϩ current [I K(leak) ] (Madison et al, 1987;McCormick and von Krosigk, 1992;Guerineau et al, 1994); (3) the slowly inactivating K ϩ current I D (Wu and Barish, 1999); (4) the delayed rectifier K ϩ current I K (Zhang et al, 1992); (5) the unspecific cationic pacemaker current (I h ) (Colino and Halliwell, 1993); (6) a Ca 2ϩ -dependent, cation-nonspecific current (Crepel et al, 1994;Greene et al, 1994;Guerineau et al, 1995;Andrade, 1997, 1999); and (7) the Ca 2ϩ -activated K ϩ current responsible for the slow afterhyperpolarization (sI AHP ) (Benardo and Prince, 1982;Nicoll, 1983, 1984;Charpak et al, 1990).…”

Acid-sensing ion channel 1a is required for mGlu receptor dependent long-term depression in the hippocampus

“…In this line, several conductance mechanisms contributing to group I mGlu receptor-mediated depolarization in CA1 pyramidal neurons have been previously described [46][47][48][49][50][51].…”