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Frequency of alcohol consumption in humans; the role of metabotropic glutamate receptors and downstream signaling pathways.

Meyers JL, Salling MC, Almli LM, Ratanatharathorn A, Uddin M, Galea S, Wildman DE, Aiello AE, Bradley B, Ressler K, Koenen KC - Transl Psychiatry (2015)

Bottom Line: Importantly, the association between several genetic variants within the mGluR-eEF2-AMPAR pathway and alcohol use behavior (i.e., consumption and alcohol-related problems) replicated in the Grady Trauma Project (GTP), an independent sample of adults living in Atlanta, Georgia (n = 1034; 95% African American), including individual variants in GRM1, GRM5, EEF2, MTOR, GRIA1, GRIA4 and HOMER2 (P < 0.05).Gene-based analyses conducted in the GTP indicated that GRM1 (empirical P < 0.05) and EEF2 (empirical P < 0.01) withstood multiple test corrections and predicted increased alcohol consumption and related problems.In conclusion, insights from rodent studies enabled the identification of novel human alcohol candidate genes within the mGluR-eEF2-AMPAR pathway.

View Article: PubMed Central - PubMed

Affiliation: Department of Epidemiology, Columbia University, New York, NY, USA.

ABSTRACT
Rodent models implicate metabotropic glutamate receptors (mGluRs) and downstream signaling pathways in addictive behaviors through metaplasticity. One way mGluRs can influence synaptic plasticity is by regulating the local translation of AMPA receptor trafficking proteins via eukaryotic elongation factor 2 (eEF2). However, genetic variation in this pathway has not been examined with human alcohol use phenotypes. Among a sample of adults living in Detroit, Michigan (Detroit Neighborhood Health Study; n = 788; 83% African American), 206 genetic variants across the mGluR-eEF2-AMPAR pathway (including GRM1, GRM5, HOMER1, HOMER2, EEF2K, MTOR, EIF4E, EEF2, CAMK2A, ARC, GRIA1 and GRIA4) were found to predict number of drinking days per month (corrected P-value < 0.01) when considered as a set (set-based linear regression conducted in PLINK). In addition, a CpG site located in the 3'-untranslated region on the north shore of EEF2 (cg12255298) was hypermethylated in those who drank more frequently (P < 0.05). Importantly, the association between several genetic variants within the mGluR-eEF2-AMPAR pathway and alcohol use behavior (i.e., consumption and alcohol-related problems) replicated in the Grady Trauma Project (GTP), an independent sample of adults living in Atlanta, Georgia (n = 1034; 95% African American), including individual variants in GRM1, GRM5, EEF2, MTOR, GRIA1, GRIA4 and HOMER2 (P < 0.05). Gene-based analyses conducted in the GTP indicated that GRM1 (empirical P < 0.05) and EEF2 (empirical P < 0.01) withstood multiple test corrections and predicted increased alcohol consumption and related problems. In conclusion, insights from rodent studies enabled the identification of novel human alcohol candidate genes within the mGluR-eEF2-AMPAR pathway.

No MeSH data available.


Related in: MedlinePlus

Simplified schema demonstrating proposed mGluR–eEF2–AMPAR pathway: Postsynaptic binding of glutamate leads to activation of ionotropic (AMPAR, NMDAR shown) and metabatropic (mGlu1/5 shown) glutamate receptors. Activation of mGlu1/5 leads to Gq activation of PLC (not shown) and the mTOR pathway that can affect the activity of Ei4FE and initiation of local RNA translation. Binding of Ca2+/CaM to EEF2K releases eEF2K-Ca/CaM complex from mGlu1/5 and scaffolding protein Homer. EEF2K-CaM phosphorylates EEF2 and switches its activity in global RNA translation to specific RNA translation including CaMK2α and Arc. CaMK2α and Arc interact with AMPARs and with downstream proteins to modulate trafficking of AMPARs in the postsynaptic membrane and regulate synaptic plasticity. AMPAR, α-amino-3-hydroxy-methyl-4-isoxasolepropionic acid receptor; CaMK2α, calcium/calmodulin-dependent protein kinase II alpha; mTOR, mechanistic target of rapamycin.
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fig1: Simplified schema demonstrating proposed mGluR–eEF2–AMPAR pathway: Postsynaptic binding of glutamate leads to activation of ionotropic (AMPAR, NMDAR shown) and metabatropic (mGlu1/5 shown) glutamate receptors. Activation of mGlu1/5 leads to Gq activation of PLC (not shown) and the mTOR pathway that can affect the activity of Ei4FE and initiation of local RNA translation. Binding of Ca2+/CaM to EEF2K releases eEF2K-Ca/CaM complex from mGlu1/5 and scaffolding protein Homer. EEF2K-CaM phosphorylates EEF2 and switches its activity in global RNA translation to specific RNA translation including CaMK2α and Arc. CaMK2α and Arc interact with AMPARs and with downstream proteins to modulate trafficking of AMPARs in the postsynaptic membrane and regulate synaptic plasticity. AMPAR, α-amino-3-hydroxy-methyl-4-isoxasolepropionic acid receptor; CaMK2α, calcium/calmodulin-dependent protein kinase II alpha; mTOR, mechanistic target of rapamycin.

Mentions: Alterations in synaptic strength are one potential physiological mechanism underlying the maladaptive learning processes associated with addiction.25, 26 One particular Group 1 mGluR (mGlu1 and 5) pathway that has gained interest in addictive disorders is the mechanism by which mGluR activation controls rapid local translation of proteins involved in long-term synaptic plasticity,27 which can occur through the phosphorylation of eukaryotic translation elongation factor 2 (eEF2; Figure 1).28, 29 Several upstream scaffolding (i.e., Homer homolog 1-2 (HOMER1-2)), and signaling proteins (i.e., mechanistic target of rapamycin (MTOR), and eEF2-kinase (eEF2K)), influence eEF2 to act as a switch from promoting global protein synthesis to the local translation of a set of proteins, such as calcium/calmodulin-dependent protein kinase II alpha, (CaMK2α) and activity-related cytoskeleton protein Arc (ARC). These proteins (CaMK2α, ARC) regulate the trafficking of α-amino-3-hydroxy-methyl-4-isoxasolepropionic acid receptors (AMPA) glutamate receptors (i.e., GRIA1-4), thereby affecting synaptic strength. Further, AMPA receptors (AMPARs), ARC and CaMK2α have independently been implicated in alcohol consumption in rodent models.30, 31, 32 Recent evidence has shown that regulating AMPAR trafficking through mGluRs in specific neural circuits can reverse addictive behaviors in rodents.33, 34 There is an abundance of evidence to suggest a link between variants in the mGluR–eEF2–AMPAR pathway and alcohol use behaviors; however, this pathway has not previously been examined in humans. Therefore, the primary goal of this study is to examine genotypic variation in the mGluR–eEF2–AMPAR pathway as it relates to alcohol use behavior in humans.


Frequency of alcohol consumption in humans; the role of metabotropic glutamate receptors and downstream signaling pathways.

Meyers JL, Salling MC, Almli LM, Ratanatharathorn A, Uddin M, Galea S, Wildman DE, Aiello AE, Bradley B, Ressler K, Koenen KC - Transl Psychiatry (2015)

Simplified schema demonstrating proposed mGluR–eEF2–AMPAR pathway: Postsynaptic binding of glutamate leads to activation of ionotropic (AMPAR, NMDAR shown) and metabatropic (mGlu1/5 shown) glutamate receptors. Activation of mGlu1/5 leads to Gq activation of PLC (not shown) and the mTOR pathway that can affect the activity of Ei4FE and initiation of local RNA translation. Binding of Ca2+/CaM to EEF2K releases eEF2K-Ca/CaM complex from mGlu1/5 and scaffolding protein Homer. EEF2K-CaM phosphorylates EEF2 and switches its activity in global RNA translation to specific RNA translation including CaMK2α and Arc. CaMK2α and Arc interact with AMPARs and with downstream proteins to modulate trafficking of AMPARs in the postsynaptic membrane and regulate synaptic plasticity. AMPAR, α-amino-3-hydroxy-methyl-4-isoxasolepropionic acid receptor; CaMK2α, calcium/calmodulin-dependent protein kinase II alpha; mTOR, mechanistic target of rapamycin.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4490281&req=5

fig1: Simplified schema demonstrating proposed mGluR–eEF2–AMPAR pathway: Postsynaptic binding of glutamate leads to activation of ionotropic (AMPAR, NMDAR shown) and metabatropic (mGlu1/5 shown) glutamate receptors. Activation of mGlu1/5 leads to Gq activation of PLC (not shown) and the mTOR pathway that can affect the activity of Ei4FE and initiation of local RNA translation. Binding of Ca2+/CaM to EEF2K releases eEF2K-Ca/CaM complex from mGlu1/5 and scaffolding protein Homer. EEF2K-CaM phosphorylates EEF2 and switches its activity in global RNA translation to specific RNA translation including CaMK2α and Arc. CaMK2α and Arc interact with AMPARs and with downstream proteins to modulate trafficking of AMPARs in the postsynaptic membrane and regulate synaptic plasticity. AMPAR, α-amino-3-hydroxy-methyl-4-isoxasolepropionic acid receptor; CaMK2α, calcium/calmodulin-dependent protein kinase II alpha; mTOR, mechanistic target of rapamycin.
Mentions: Alterations in synaptic strength are one potential physiological mechanism underlying the maladaptive learning processes associated with addiction.25, 26 One particular Group 1 mGluR (mGlu1 and 5) pathway that has gained interest in addictive disorders is the mechanism by which mGluR activation controls rapid local translation of proteins involved in long-term synaptic plasticity,27 which can occur through the phosphorylation of eukaryotic translation elongation factor 2 (eEF2; Figure 1).28, 29 Several upstream scaffolding (i.e., Homer homolog 1-2 (HOMER1-2)), and signaling proteins (i.e., mechanistic target of rapamycin (MTOR), and eEF2-kinase (eEF2K)), influence eEF2 to act as a switch from promoting global protein synthesis to the local translation of a set of proteins, such as calcium/calmodulin-dependent protein kinase II alpha, (CaMK2α) and activity-related cytoskeleton protein Arc (ARC). These proteins (CaMK2α, ARC) regulate the trafficking of α-amino-3-hydroxy-methyl-4-isoxasolepropionic acid receptors (AMPA) glutamate receptors (i.e., GRIA1-4), thereby affecting synaptic strength. Further, AMPA receptors (AMPARs), ARC and CaMK2α have independently been implicated in alcohol consumption in rodent models.30, 31, 32 Recent evidence has shown that regulating AMPAR trafficking through mGluRs in specific neural circuits can reverse addictive behaviors in rodents.33, 34 There is an abundance of evidence to suggest a link between variants in the mGluR–eEF2–AMPAR pathway and alcohol use behaviors; however, this pathway has not previously been examined in humans. Therefore, the primary goal of this study is to examine genotypic variation in the mGluR–eEF2–AMPAR pathway as it relates to alcohol use behavior in humans.

Bottom Line: Importantly, the association between several genetic variants within the mGluR-eEF2-AMPAR pathway and alcohol use behavior (i.e., consumption and alcohol-related problems) replicated in the Grady Trauma Project (GTP), an independent sample of adults living in Atlanta, Georgia (n = 1034; 95% African American), including individual variants in GRM1, GRM5, EEF2, MTOR, GRIA1, GRIA4 and HOMER2 (P < 0.05).Gene-based analyses conducted in the GTP indicated that GRM1 (empirical P < 0.05) and EEF2 (empirical P < 0.01) withstood multiple test corrections and predicted increased alcohol consumption and related problems.In conclusion, insights from rodent studies enabled the identification of novel human alcohol candidate genes within the mGluR-eEF2-AMPAR pathway.

View Article: PubMed Central - PubMed

Affiliation: Department of Epidemiology, Columbia University, New York, NY, USA.

ABSTRACT
Rodent models implicate metabotropic glutamate receptors (mGluRs) and downstream signaling pathways in addictive behaviors through metaplasticity. One way mGluRs can influence synaptic plasticity is by regulating the local translation of AMPA receptor trafficking proteins via eukaryotic elongation factor 2 (eEF2). However, genetic variation in this pathway has not been examined with human alcohol use phenotypes. Among a sample of adults living in Detroit, Michigan (Detroit Neighborhood Health Study; n = 788; 83% African American), 206 genetic variants across the mGluR-eEF2-AMPAR pathway (including GRM1, GRM5, HOMER1, HOMER2, EEF2K, MTOR, EIF4E, EEF2, CAMK2A, ARC, GRIA1 and GRIA4) were found to predict number of drinking days per month (corrected P-value < 0.01) when considered as a set (set-based linear regression conducted in PLINK). In addition, a CpG site located in the 3'-untranslated region on the north shore of EEF2 (cg12255298) was hypermethylated in those who drank more frequently (P < 0.05). Importantly, the association between several genetic variants within the mGluR-eEF2-AMPAR pathway and alcohol use behavior (i.e., consumption and alcohol-related problems) replicated in the Grady Trauma Project (GTP), an independent sample of adults living in Atlanta, Georgia (n = 1034; 95% African American), including individual variants in GRM1, GRM5, EEF2, MTOR, GRIA1, GRIA4 and HOMER2 (P < 0.05). Gene-based analyses conducted in the GTP indicated that GRM1 (empirical P < 0.05) and EEF2 (empirical P < 0.01) withstood multiple test corrections and predicted increased alcohol consumption and related problems. In conclusion, insights from rodent studies enabled the identification of novel human alcohol candidate genes within the mGluR-eEF2-AMPAR pathway.

No MeSH data available.


Related in: MedlinePlus