G‐protein‐mediated desensitization of metabotropic glutamatergic and muscarinic responses in CA3 cells in rat hippocampus.

Abstract

1. Desensitization of a metabotropic response was investigated in CA3 pyramidal neurons in hippocampal slice cultures using the patch‐clamp technique. 2. 1S,3R‐1‐aminocyclopentane‐1,3‐dicarboxylate (1S,3R‐ACPD), an agonist at metabotropic glutamate receptors (mGluRs), and metacholine (MCh), an agonist at muscarinic receptors, induced a cationic current that appears to be activated through a G‐protein‐independent transduction process, as previously shown. Prolonged or repetitive bath application of agonists led to rapid desensitization of the cationic current with a time constant of approximately 20 s. 3. Complete recovery from desensitization was observed within 6 min. 4. These responses mediated by mGluRs and muscarinic receptors cross‐desensitized. 5. Preventing the activation of G‐proteins by loading cells with GDP beta S strongly reduced or suppressed desensitization, and resulted in a sustained inward cationic current. When cells were filled with GTP gamma S to irreversibly activate G‐proteins, the desensitization process was enhanced such that a first application of agonist caused a markedly reduced response. 6. These results show that a cationic current induced by metabotropic agonists in hippocampal pyramidal cells undergoes apparent desensitization and suggests that this process occurs through a G‐protein‐mediated inhibition of the underlying membrane conductance.

Group I Metabotropic Glutamate Receptor (mGluR)-Dependent Long-Term Depression Mediated via p38 Mitogen-Activated Protein Kinase Is Inhibited by Previous High-Frequency Stimulation and Activation of mGluRs and Protein Kinase C in the Rat Dentate GyrusIn Vitro

“…The most likely mechanism of such inhibition of LTD induction is a PKC-mediated inactivation of group I mGluRs via a classical feedback loop, with the activation of mGluRs by the preconditioning HFS resulting in stimulation of PKC and subsequent inactivation of the group I mGluRs. One possible way in which this could occur is by desensitization, because desensitization of group I mGluRs by mGluRmediated stimulation of PKC is a well known phenomenon (Schoepp and Johnson, 1988;Guerineau et al, 1997;Gereau and Heinemann, 1998;Alagarsamy et al, 1999). Moreover, analysis of PKC phosphorylation site mutants has revealed several sites, including most effectively, serine/threonine 881 and 890, at which desensitization of mGluR5 occurs (Gereau and Heinemann, 1998).…”

Distinct physiological roles of the Gq‐coupled metabotropic glutamate receptors co‐expressed in the same neuronal populations

“…With repeated or prolonged agonist application, the group I mGluRs have been observed to undergo homologous desensitization in a variety of native and recombinant systems (Schoepp and Johnson, 1988; Manzoni et al, 1990; Catania et al, 1991; Balazs et al, 1997; Guerineau et al, 1997; Peavy and Conn, 1998; Alagarsamy et al, 1999). The phospholipid‐ and calcium‐dependent protein kinase C (PKC) has been clearly implicated in this desensitization (Schoepp and Johnson, 1988; Manzoni et al, 1990; Catania et al, 1991; Gereau and Heinemann, 1998; Alagarsamy et al, 1999; Ciruela et al, 1999a).…”

Sonic hedgehog is a neuromodulator in the adult subthalamic nucleus

“…Briefly, after killing by cervical dislocation, the rats were decapitated, brains were rapidly removed, and a block of cerebral matter containing the STN was isolated in an ice-cold sucrose-enriched solution. After a 2 h recovery period in a Krebs' solution containing (in mM): 124 NaCl, 26 NaHCO 3 , 3.6 KCl, 1.3 MgCl 2 , 2.4 CaCl 2 , 1.25 HEPES, and 10 glucose (pH 7.4), bubbled with 95% O 2 and 5% CO 2 ; one slice was transferred to an immersion-type recording chamber (21) and continuously superfused (3.5 ml/min) with the oxygenated Krebs' solution. The slice was examined under a dissecting microscope; STN was readily identified as ovoid gray matter immediately dorsal to the cerebral peduncle.…”