Dynamic regulation of homer binding to group i metabotropic glutamate receptors by preso1 and converging kinase cascades

Jia Hua Hu, Paul F Worley, Paul J. Kammermeier

Research output: Contribution to journalArticle

Abstract

In rat sympathetic neurons from the superior cervical ganglia (SCG) expressing metabotropic glutamate receptor mGluR1 or mGluR5, overexpression of scaffolding Homer proteins, which bind to a Homer ligand in their C termini, cause receptor clustering and uncoupling from ion channel modulation. In the absence of recombinant Homer protein overexpression, uncoupling of mGluRs from voltage-dependent channels can be induced by expression of Preso1, an adaptor of prolinedirected kinases that phosphorylates the Homer ligand and recruits binding of endogenous Homer proteins. Here we show that in SCG neurons expressing mGluR1 and the tyrosine receptor kinase B, treatment with brain-derived neurotrophic factor (BDNF) produces a similar uncoupling of the receptors from calcium channels. We investigated the pathways that mediate this uncoupling and compared it with uncoupling observed with Preso1 expression. Both BDNF- and Preso1- induced uncoupling require residues T1151 and S1154 in the mGluR1 Homer ligand (TPPSPF). Uncoupling via Preso1 but not BDNF was prevented by expression of a dominant negative Cdk5, suggesting that endogenous Cdk5 mediates Preso1- dependent phosphorylation of mGluR1. Dominant negative Cdk5 did not block the BDNF effect but this was sensitive to inhibitors of the mitogen-activated protein kinase kinase/extracellular signal-regulated kinase cascade. Interestingly, the BDNF pathway appeared to require native Preso1 binding to mGluR, because overexpression of the Preso1 FERM domain, which mediates the Preso1-mGluR interaction, prevented BDNF-induced uncoupling. These data suggest that the BDNF/tyrosine receptor kinase B and Cdk5 pathways converge at the level of mGluR to similarly induce Homer ligand phosphorylation, recruit Homer binding, and uncouple mGluRs from channel regulation.

Original languageEnglish (US)
Pages (from-to)122-129
Number of pages8
JournalJournal of Pharmacology and Experimental Therapeutics
Volume361
Issue number1
DOIs
StatePublished - Apr 1 2017

Fingerprint

Metabotropic Glutamate Receptors
Brain-Derived Neurotrophic Factor
Phosphotransferases
Ligands
Superior Cervical Ganglion
Phosphorylation
trkB Receptor
Neurons
Mitogen-Activated Protein Kinase Kinases
Extracellular Signal-Regulated MAP Kinases
Receptor Protein-Tyrosine Kinases
Calcium Channels
Ion Channels
Recombinant Proteins
Protein-Tyrosine Kinases
Cluster Analysis
metabotropic glutamate receptor type 1
Homer Scaffolding Proteins

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

Cite this

Dynamic regulation of homer binding to group i metabotropic glutamate receptors by preso1 and converging kinase cascades. / Hu, Jia Hua; Worley, Paul F; Kammermeier, Paul J.

In: Journal of Pharmacology and Experimental Therapeutics, Vol. 361, No. 1, 01.04.2017, p. 122-129.

Research output: Contribution to journalArticle

@article{2608f78b37d24e5f8f49bb02aeef6238,
title = "Dynamic regulation of homer binding to group i metabotropic glutamate receptors by preso1 and converging kinase cascades",
abstract = "In rat sympathetic neurons from the superior cervical ganglia (SCG) expressing metabotropic glutamate receptor mGluR1 or mGluR5, overexpression of scaffolding Homer proteins, which bind to a Homer ligand in their C termini, cause receptor clustering and uncoupling from ion channel modulation. In the absence of recombinant Homer protein overexpression, uncoupling of mGluRs from voltage-dependent channels can be induced by expression of Preso1, an adaptor of prolinedirected kinases that phosphorylates the Homer ligand and recruits binding of endogenous Homer proteins. Here we show that in SCG neurons expressing mGluR1 and the tyrosine receptor kinase B, treatment with brain-derived neurotrophic factor (BDNF) produces a similar uncoupling of the receptors from calcium channels. We investigated the pathways that mediate this uncoupling and compared it with uncoupling observed with Preso1 expression. Both BDNF- and Preso1- induced uncoupling require residues T1151 and S1154 in the mGluR1 Homer ligand (TPPSPF). Uncoupling via Preso1 but not BDNF was prevented by expression of a dominant negative Cdk5, suggesting that endogenous Cdk5 mediates Preso1- dependent phosphorylation of mGluR1. Dominant negative Cdk5 did not block the BDNF effect but this was sensitive to inhibitors of the mitogen-activated protein kinase kinase/extracellular signal-regulated kinase cascade. Interestingly, the BDNF pathway appeared to require native Preso1 binding to mGluR, because overexpression of the Preso1 FERM domain, which mediates the Preso1-mGluR interaction, prevented BDNF-induced uncoupling. These data suggest that the BDNF/tyrosine receptor kinase B and Cdk5 pathways converge at the level of mGluR to similarly induce Homer ligand phosphorylation, recruit Homer binding, and uncouple mGluRs from channel regulation.",
author = "Hu, {Jia Hua} and Worley, {Paul F} and Kammermeier, {Paul J.}",
year = "2017",
month = "4",
day = "1",
doi = "10.1124/jpet.116.238394",
language = "English (US)",
volume = "361",
pages = "122--129",
journal = "Journal of Pharmacology and Experimental Therapeutics",
issn = "0022-3565",
publisher = "American Society for Pharmacology and Experimental Therapeutics",
number = "1",

}

TY - JOUR

T1 - Dynamic regulation of homer binding to group i metabotropic glutamate receptors by preso1 and converging kinase cascades

AU - Hu, Jia Hua

AU - Worley, Paul F

AU - Kammermeier, Paul J.

PY - 2017/4/1

Y1 - 2017/4/1

N2 - In rat sympathetic neurons from the superior cervical ganglia (SCG) expressing metabotropic glutamate receptor mGluR1 or mGluR5, overexpression of scaffolding Homer proteins, which bind to a Homer ligand in their C termini, cause receptor clustering and uncoupling from ion channel modulation. In the absence of recombinant Homer protein overexpression, uncoupling of mGluRs from voltage-dependent channels can be induced by expression of Preso1, an adaptor of prolinedirected kinases that phosphorylates the Homer ligand and recruits binding of endogenous Homer proteins. Here we show that in SCG neurons expressing mGluR1 and the tyrosine receptor kinase B, treatment with brain-derived neurotrophic factor (BDNF) produces a similar uncoupling of the receptors from calcium channels. We investigated the pathways that mediate this uncoupling and compared it with uncoupling observed with Preso1 expression. Both BDNF- and Preso1- induced uncoupling require residues T1151 and S1154 in the mGluR1 Homer ligand (TPPSPF). Uncoupling via Preso1 but not BDNF was prevented by expression of a dominant negative Cdk5, suggesting that endogenous Cdk5 mediates Preso1- dependent phosphorylation of mGluR1. Dominant negative Cdk5 did not block the BDNF effect but this was sensitive to inhibitors of the mitogen-activated protein kinase kinase/extracellular signal-regulated kinase cascade. Interestingly, the BDNF pathway appeared to require native Preso1 binding to mGluR, because overexpression of the Preso1 FERM domain, which mediates the Preso1-mGluR interaction, prevented BDNF-induced uncoupling. These data suggest that the BDNF/tyrosine receptor kinase B and Cdk5 pathways converge at the level of mGluR to similarly induce Homer ligand phosphorylation, recruit Homer binding, and uncouple mGluRs from channel regulation.

AB - In rat sympathetic neurons from the superior cervical ganglia (SCG) expressing metabotropic glutamate receptor mGluR1 or mGluR5, overexpression of scaffolding Homer proteins, which bind to a Homer ligand in their C termini, cause receptor clustering and uncoupling from ion channel modulation. In the absence of recombinant Homer protein overexpression, uncoupling of mGluRs from voltage-dependent channels can be induced by expression of Preso1, an adaptor of prolinedirected kinases that phosphorylates the Homer ligand and recruits binding of endogenous Homer proteins. Here we show that in SCG neurons expressing mGluR1 and the tyrosine receptor kinase B, treatment with brain-derived neurotrophic factor (BDNF) produces a similar uncoupling of the receptors from calcium channels. We investigated the pathways that mediate this uncoupling and compared it with uncoupling observed with Preso1 expression. Both BDNF- and Preso1- induced uncoupling require residues T1151 and S1154 in the mGluR1 Homer ligand (TPPSPF). Uncoupling via Preso1 but not BDNF was prevented by expression of a dominant negative Cdk5, suggesting that endogenous Cdk5 mediates Preso1- dependent phosphorylation of mGluR1. Dominant negative Cdk5 did not block the BDNF effect but this was sensitive to inhibitors of the mitogen-activated protein kinase kinase/extracellular signal-regulated kinase cascade. Interestingly, the BDNF pathway appeared to require native Preso1 binding to mGluR, because overexpression of the Preso1 FERM domain, which mediates the Preso1-mGluR interaction, prevented BDNF-induced uncoupling. These data suggest that the BDNF/tyrosine receptor kinase B and Cdk5 pathways converge at the level of mGluR to similarly induce Homer ligand phosphorylation, recruit Homer binding, and uncouple mGluRs from channel regulation.

UR - http://www.scopus.com/inward/record.url?scp=85018522300&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85018522300&partnerID=8YFLogxK

U2 - 10.1124/jpet.116.238394

DO - 10.1124/jpet.116.238394

M3 - Article

C2 - 28179473

AN - SCOPUS:85018522300

VL - 361

SP - 122

EP - 129

JO - Journal of Pharmacology and Experimental Therapeutics

JF - Journal of Pharmacology and Experimental Therapeutics

SN - 0022-3565

IS - 1

ER -