On the basis of sequence homology and structural similarities, metabotropic glutamate receptors (mGluRs), extracellular Ca 2؉ -sensing receptor, ␥-aminobutyric acid type B receptor, and pheromone receptors are enlisted in a distinct family within the larger G proteincoupled receptor superfamily. When expressed in heterologous systems, group I mGluRs can activate dual signal transduction pathways, phosphoinositides turnover and cAMP production. To investigate the structural basis of these coupling properties, we introduced single amino acid substitutions within the second and third intracellular loops (i2 and i3) of mGluR1␣. Metabotropic glutamate receptors (mGluRs)1 are coupled to heterotrimeric G proteins, and through this interaction they regulate the intracellular level of second messenger molecules such as inositol trisphosphate and cyclic AMP (cAMP). Furthermore, they have been shown to modulate the activity of voltage-sensitive Ca 2ϩ and K ϩ channels, G protein-regulated inward rectifier K ϩ channels, as well as GABA A , ␣-amino-3-hydroxy-5-methylisoxazole-4-propionate, and N-methyl-D-aspartate receptors (1-2). Thus far, eight mGluRs (mGluR1 through mGluR8; see Refs. 3-10) have been cloned. They have been categorized into three groups according to their sequence homology, agonist selectivity, and main signal transduction pathway activated in heterologous systems (1,(11)(12). Group I mGluRs (mGluR1 and -5) mobilize intracellular Ca 2ϩ by stimulating phosphoinositide (PI) turnover and promote cAMP accumulation; group II (mGluR2 and 3) and group III (mGluR4, -6 -8) receptors inhibit adenylyl cyclase. mGluRs, together with the parathyroid Ca 2ϩ -sensing receptors (PCaR1 (13)) and the GABA B receptor (14), form a separate family within the seven transmembrane domain G protein-coupled receptor (GPCR) superfamily (15-17). mGluRs are characterized by a large amino-terminal extracellular domain that comprises the glutamate binding site (18 -19). The intracellular loops connecting the putative membrane-spanning helices are also distinctive. In mGluRs, they are relatively small compared with those of seven transmembrane domain receptors belonging to the rhodopsin/-adrenergic family. Most importantly, there is no significant sequence homology between members of the mGluR family and other cloned GPCRs.The structure-function relationships supporting the coupling to G proteins have been well investigated for members of the rhodopsin/-adrenergic family. Although all the cytoplasmic domains of these receptors take part in G protein activation to some degree, i3 appears to harbor the structural elements that impart specificity to the interaction (20 -21).However, much less is known about the structural determinants of the coupling of mGluRs to G proteins. Recently, the analysis of chimeric receptors derived from the G i -coupled mGluR3 bearing different portions of the cytoplasmic domains of the G q -coupled mGluR1 has shown that i2 of group I receptors is necessary, but not sufficient, for the specific activation of pho...
Signaling by the metabotropic glutamate receptor 1␣ (mGluR1␣) can lead to the accumulation of inositol 1,4,5-trisphosphate (InsP 3) and cAMP and to the modulation of K ؉ and Ca 2؉ channel opening. At present, very little is known about how these different actions are integrated and eventually turned off. Unraveling the molecular mechanisms underlying these functions is crucial for understanding mGluR-mediated regulation of synaptic transmission. It has been shown that receptor-induced activation of the InsP 3 pathway is subject to feedback inhibition mediated by protein kinase C (PKC). In this study, we provide evidence for a differential regulation by PKC and protein kinase A of two distinct mGluR1␣-dependent signaling pathways. PKC activation selectively inhibits agonist-dependent stimulation of the InsP 3 pathway but does not affect receptor signaling via cAMP. In contrast, protein kinase A potentiates agonist-independent signaling of the receptor via InsP 3. Furthermore, we demonstrate that the selectivity of PKC action on receptor signaling rests on phosphorylation of a threonine residue located in the G protein-interacting domain of the receptor. Modification at Thr 695 selectively disrupts mGluR1␣-Gq/11 interaction without affecting signaling through Gs. Together, these data provide insight on the mechanisms by which selective downregulation of a specific receptor-dependent signaling pathway can be achieved and on how cross-talk between different second messenger cascades may contribute to fine-tune short-and longterm receptor activity.T he excitatory actions of glutamate in the central nervous system are mediated by two distinct classes of receptors: ionotropic and metabotropic. While ionotropic receptors drive fast neurotransmission, the stimulation of metabotropic glutamate receptors generates slower and longer lasting changes in the signaling cascades activated in neuronal and glial cells. Metabotropic glutamate receptors (mGluRs; mGluR1 through mGluR8) are classified into three distinct groups according to their sequence homology, pharmacological profile, and signaling properties; group I receptors are linked to phosphoinositide metabolism while groups II and III inhibit adenylyl cyclase (1, 2). Many functions have been ascribed to these receptors, such as regulation of neurotransmitter release, direct mediation of glutamatergic synaptic transmission, modulation of membrane excitability, and regulation of N-methyl-D-aspartate, ␣-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid, and ␥-aminobutyric acid type A receptor activity (1). This vast array of effects underscores the role of mGluRs in modulating synaptic plasticity and their neurotoxic as well as neuroprotective action (1, 3).As for other G protein-coupled receptors (GPCRs), mGluRs induce diverse and long-lasting cellular responses; these actions depend on the effectors regulated by each second messenger molecule and on the cross-talk between signaling pathways. In the past several years, it has become increasingly clear that many GPCRs can i...
Precise targeting of neurotransmitter receptors to different neuronal compartments is a fundamental step for the establishment and function of synaptic circuitry. Group I metabotropic glutamate receptors, mGluR1 and mGluR5, control glutamatergic neurotransmission by acting both postsynaptically and presynaptically. Four alternatively spliced variants of the mGluR1 gene exist, which differ in their signaling properties and subcellular localization. The present study was undertaken to identify the molecular signals responsible for trafficking of these receptors to different neuronal compartments. Here we report that targeting of mGluR1 to dendrites and axons of transfected retina neurons is controlled by alternative splicing. We have identified in the tail of the receptor a tripeptide motif, which is necessary and sufficient to exclude the splice variant mGluR1b from distal dendrites and to drive it to the axon. This motif, which is present in all the mGluR1 receptors, is masked in mGluR1a by a dominant dendritic signal sequence harbored by the extended C-terminal tail of this splice variant. Furthermore, we show that the identified axonal and dendritic targeting signals are also necessary and sufficient to localize mGluR1b and mGluR1a to the apical and basolateral compartment of Madin-Darby canine kidney cells, respectively, consistent with the existence of common trafficking components for polarized targeting in epithelial cells and neurons.
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