Abstract
It is well-appreciated that phosphorylation is an essential post-translational mechanism of regulation for several proteins, including group 1 metabotropic glutamate receptors (mGluRI), mGluR1, and mGluR5 subtypes. While contributions of various serine/threonine protein kinases on mGluRI modulation have been recognized, the functional role of tyrosine kinases (TKs) is less acknowledged. Here, while describing current evidence supporting that mGluRI are targets of TKs, we mainly focus on the modulatory roles of the ErbB tyrosine kinases receptors—activated by the neurotrophic factors neuregulins (NRGs)—on mGluRI function. Available evidence suggests that mGluRI activity is tightly dependent on ErbB signaling, and that ErbB’s modulation profoundly influences mGluRI-dependent effects on neurotransmission, neuronal excitability, synaptic plasticity, and learning and memory processes.
Highlights
Group 1 metabotropic glutamate receptors are G protein-coupled receptors (GPCR) comprising two closely related subtypes: mGluR1 (GRM1) and mGluR5 (GRM5). mGluR1 exist in four isoforms whereas mGluR5 exist in three variants; different isoforms are produced by alternative genetic splicing and mainly differ for C-terminal intracellular tail [1,2,3]
Canonical mGluRI signaling is mediated by Gq/11-activated pathways, mainly resulting in the activation of phospholipase C β (PLCβ), which mediates the hydrolysis of phosphatidylinositol and generation of inositol-1,4,5-trisphosphate (IP3) and diacylglycerol (DAG), leading to Ca2+ intracellular mobilization from internal stores and activation of protein kinase C (PKC) [2]
MGluRI stimulation can activate a list of effectors, including phospholipase D (PLD), protein kinases pathways such as casein kinase 1 (CK1), cyclin-dependent protein kinase 5 (CDK5), components of the family of the mitogen-activated protein kinases (MAPK), like extracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK), as well as phosphatidylinositol
Summary
Investigations on the subcellular localization of ErbB4, the most studied ErbB subunit, have revealed their preferential localization in the glutamatergic postsynaptic densities (PSD), where they interact with PSD-95 [56,62,63], which is an important scaffolding hub leading glutamatergic post-synapse architecture, by docking glutamatergic receptors, both ionotropic NMDAR and AMPARs, or mGluRs, mainly mGluRI, directly or by association to other proteins. Neo-synthesized mGluR1 are quickly distributed to surface membrane of midbrain DA neurons, and efficiently associate with their intracellular effectors, as proven by potentiated mGluR1 function (i.e., mGluR1-mediated inward currents) in single DA neurons following NRG1-induced ErbB activation Such an increase in mGluR1-mediated inward currents in DA cells, by ErbB stimulation is prevented by protein synthesis inhibition, with drugs like anisomycin or cycloheximide [51]. It will be interesting to investigate if discrete ErbB dimers predominate in the control of mGluR1 and mGluR5 functions in different brain areas or cellular populations, as well as in the activation of discrete mGluRI signaling pathways To this regard, an earlier report documented that mGluRI-dependent ERK2 activation is regulated by ErbB1, but not ErbB2, in rat astrocytes cultures [46], whereas the contribution of ErbB2 is clearly demonstrated in the 9 of 17 9 of 18 re[4g6u]l,awtihoneroeaf svtahreiocuosnmtriGbluutRioInfuonf cEtriobnBs2 eisitchleerarinlyrdatemmoidnbsrtraaintedDAinntheue rroengsuloartiionnmoof uvsaerihoiupspmocGalmuRpaI l CfAun1cptiyornasmeiidthaelrcienllrsa[t5m1–i5d3b]r.ain DA neurons or in mouse hippocampal CA1 pyramidal cells [51,52,53]. ErbB2-ErbB4 dimers, expressed on DA neurons, are the best candidate involved in the regulation of mGluR1-dependent LTD, as shown by ErbB inhibition in single DA neurons with different drugs [52,54]
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