Control of neuronal excitability by Group I metabotropic glutamate receptors

Abstract

Metabotropic glutamate (mGlu) receptors couple through G proteins to regulate a large number of cell functions. Eight mGlu receptor isoforms have been cloned and classified into three Groups based on sequence, signal transduction mechanisms and pharmacology. This review will focus on Group I mGlu receptors, comprising the isoforms mGlu 1 and mGlu 5 . Activation of these receptors initiates both G protein-dependent and -independent signal transduction pathways. The G-protein-dependent pathway involves mainly Gα q , which can activate PLCβ, leading initially to the formation of IP 3 and diacylglycerol. IP 3 can release Ca 2+ from cellular stores resulting in activation of Ca 2+ -dependent ion channels. Intracellular Ca 2+ , together with diacylglycerol, activates PKC, which has many protein targets, including ion channels. Thus, activation of the G-protein-dependent pathway affects cellular excitability though several different effectors. In parallel, G protein-independent pathways lead to activation of non-selective cationic currents and metabotropic synaptic currents and potentials. Here, we provide a survey of the membrane transport proteins responsible for these electrical effects of Group I metabotropic glutamate receptors.

Group I mGluR-Mediated Activation of Martinotti Cells Inhibits Local Cortical Circuitry in Human Cortex

“…Since group I mGluRs are located mostly perisynaptically and can therefore likely be activated by spillover of glutamate from the synaptic cleft (Luján et al, 1996), subsequent depolarization of these interneuron types may constitute a mechanism by which inhibition is increased upon a prolonged or very strong initial excitatory drive. Group I mGluR activation can alter neuronal excitability through a variety of differing mechanisms, including protein kinase C-mediated changes upon ion channels, or through calcium-dependent modulation of ion channels (Correa et al, 2017). mGluRs have been proposed to be involved in epileptogenesis (McNamara et al, 2006) and group I mGluRs are upregulated in the hippocampus of patients with temporal lobe epilepsy (Blümcke et al, 2000).…”

The G Protein-Coupled Glutamate Receptors as Novel Molecular Targets in Schizophrenia Treatment—A Narrative Review

“…Because mGluRs of group I are located predominantly postsynaptically, their activation results in neuronal depolarization, although mGluR1′s ability to elicit hyperpolarization was demonstrated in midbrain dopaminergic neurons [ 15 ]. Of relevance to schizophrenia, mGluR1/5 can influence both post- and presynaptic NMDA receptor currents, and this bidirectional regulation depends on calcium [ 31 ]. When intracellular Ca 2+ concentration rises, activation of mGluR1/5 decreases NMDA receptor activity to provide control over abnormal, and potentially detrimental, Ca 2+ increases.…”

Canais iônicos que governam o disparo espontâneo dos neurônios Cartwheel do núcleo coclear dorsal

“…Neste experimento verificamos se o agonista mGluR1 e mGluR5 DHPG (S-3,5-Dihidroxifenilglicina) produz efeitos sobre a I h (a partir da ativação dos receptores mGluR1), particularmente se a modula positivamente, como ocorre nos neurônios Purkinje cerebelares (Correa et al, 2017 Figura 4.10.1. Exemplos de respostas de corrente aos primeiros 300 milisegundos dos pulsos de -80mV a -50mV do protocolo IV, para o neurônio Active (A) e Quiet (B) mencionados no texto, antes (i) e após (ii) aplicação do níquel 50M.…”

“…O perfil atípico (não-linear) da dependência do sag em relação à magnitude da corrente hiperpolarizante injetada, mostrado na Fig. 4.8.3 (Correa et al, 2017;Shim et al, 2016), porém como descrito na seção…”

“…Em nosso experimento com o DHPG, os registros em Voltage-Clamp mostraram claramente que I h nos neurônios CW não é modulada pela ativação de receptores mGluR1, como ocorre nos neurônios Purkinje cerebelares (Correa et al, 2017). O perfil muito incomum/atípico da corrente sensível ao DHPG que obtemos não se assemelha ao perfil de qualquer corrente subliminar por nos conhecida (Fig.…”