Skip to main content

Activation of mGluR5 Induces Rapid and Long-Lasting Protein Kinase D Phosphorylation in Hippocampal Neurons


Metabotropic glutamate receptors (mGluRs), including mGluR5, play a central role in regulating the strength and plasticity of synaptic connections in the brain. However, the signaling pathways that connect mGluRs to their downstream effectors are not yet fully understood. Here, we report that stimulation of mGluR5 in hippocampal cultures and slices results in phosphorylation of protein kinase D (PKD) at the autophosphorylation site Ser-916. This phosphorylation event occurs within 30 s of stimulation, persists for at least 24 h, and is dependent on activation of phospholipase C and protein kinase C. Our data suggest that activation of PKD may represent a novel signaling pathway linking mGluR5 to its downstream targets. These findings have important implications for the study of the molecular mechanisms underlying mGluR-dependent synaptic plasticity.

This is a preview of subscription content, access via your institution.

Figure 1
Figure 2
Figure 3



Artificial cerebrospinal fluid


Analysis of variance






Metabotropic glutamate receptor


Protein kinase C


Protein kinase D


Phospholipase C


  • Avkiran M, Rowland AJ, Cuello F, Haworth RS (2008) Protein kinase D in the cardiovascular system: emerging roles in health and disease. Circ Res 102:157–163

    Article  CAS  PubMed  Google Scholar 

  • Bisbal M, Conde C, Donoso M, Bollati F, Sesma J, Quiroga S, Diaz Anel A, Malhotra V, Marzolo MP, Caceres A (2008) Protein kinase D regulates trafficking of dendritic membrane proteins in developing neurons. J Neurosci 28:9297–9308

    Article  CAS  PubMed  Google Scholar 

  • Chen WS, Bear MF (2007) Activity-dependent regulation of NR2B translation contributes to metaplasticity in mouse visual cortex. Neuropharmacology 52:200–214

    Article  CAS  PubMed  Google Scholar 

  • Cohen AS, Abraham WC (1996) Facilitation of long-term potentiation by prior activation of metabotropic glutamate receptors. J Neurophysiol 76:953–962

    CAS  PubMed  Google Scholar 

  • Conn PJ (2003) Physiological roles and therapeutic potential of metabotropic glutamate receptors. Ann N Y Acad Sci 1003:12–21

    Article  CAS  PubMed  Google Scholar 

  • Czondor K, Ellwanger K, Fuchs YF, Lutz S, Gulyas M, Mansuy IM, Hausser A, Pfizenmaier K, Schlett K (2009) Protein kinase D controls the integrity of Golgi apparatus and the maintenance of dendritic arborization in hippocampal neurons. Mol Biol Cell 20:2108–2120

    Article  CAS  PubMed  Google Scholar 

  • Dolen G, Osterweil E, Rao BSS, Smith GB, Auerbach BD, Chattarji S, Bear MF (2007) Correction of fragile X syndrome in mice. Neuron 56:955–962

    Article  CAS  PubMed  Google Scholar 

  • Gerber U, Gee CE, Benquet P (2007) Metabotropic glutamate receptors: intracellular signaling pathways. Curr Opin Pharmacol 7:56–61

    Article  CAS  PubMed  Google Scholar 

  • Huber KM, Kayser MS, Bear MF (2000) Role for rapid dendritic protein synthesis in hippocampal mGluR-dependent long-term depression. Science 288:1254–1256

    Article  CAS  PubMed  Google Scholar 

  • Huber KM, Roder JC, Bear MF (2001) Chemical induction of mGluR5- and protein synthesis-dependent long-term depression in hippocampal area CA1. J Neurophysiol 86:321–325

    CAS  PubMed  Google Scholar 

  • Iglesias T, Waldron RT, Rozengurt E (1998) Identification of in vivo phosphorylation sites required for protein kinase D activation. J Biol Chem 273:27662–27667

    Article  CAS  PubMed  Google Scholar 

  • Ireland DR, Abraham WC (2002) Group I mGluRs increase excitability of hippocampal CA1 pyramidal neurons by a PLC-independent mechanism. J Neurophysiol 88:107–116

    CAS  PubMed  Google Scholar 

  • Johannes FJ, Prestle J, Eis S, Oberhagemann P, Pfizenmaier K (1994) PKCu is a novel, atypical member of the protein kinase C family. J Biol Chem 269:6140–6148

    CAS  PubMed  Google Scholar 

  • Krueger DD, Nairn AC (2007) Expression of PKC substrate proteins, GAP-43 and neurogranin, is downregulated by cAMP signaling and alterations in synaptic activity. Eur J NeuroSci 26:3043–3053

    Article  PubMed  Google Scholar 

  • Malenka RC, Bear MF (2004) LTP and LTD: an embarrassment of riches. Neuron 44:5–21

    Article  CAS  PubMed  Google Scholar 

  • Matthews SA, Rozengurt E, Cantrell D (1999) Characterization of serine 916 as an in vivo autophosphorylation site for protein kinase D/protein kinase C++. J Biol Chem 274:26543–26549

    Article  CAS  PubMed  Google Scholar 

  • Mellentin C, Jahnsen H, Abraham WC (2007) Priming of long-term potentiation mediated by ryanodine receptor activation in rat hippocampal slices. Neuropharmacology 52:118–125

    Article  CAS  PubMed  Google Scholar 

  • Netzeband JG, Parsons KL, Sweeney DD, Gruol DL (1997) Metabotropic glutamate receptor agonists alter neuronal excitability and Ca2+ levels via the phospholipase C transduction pathway in cultured Purkinje neurons. J Neurophysiol 78:63–75

    CAS  PubMed  Google Scholar 

  • Oliet SHR, Malenka RC, Nicoll RA (1997) Two distinct forms of long-term depression coexist in CA1 hippocampal pyramidal cells. Neuron 18:969–982

    Article  CAS  PubMed  Google Scholar 

  • Rozengurt E, Rey O, Waldron RT (2005) Protein kinase D signaling. J Biol Chem 280:13205–13208

    Article  CAS  PubMed  Google Scholar 

  • Valverde AM, Sinnett-Smith J, Van LJ, Rozengurt E (1994) Molecular cloning and characterization of protein kinase D: a target for diacylglycerol and phorbol esters with a distinctive catalytic domain. Proc Natl Acad Sci USA 91:8572–8576

    Article  CAS  PubMed  Google Scholar 

  • Yin DM, Huang YH, Zhu YB, Wang Y (2008) Both the establishment and maintenance of neuronal polarity require the activity of protein kinase D in the Golgi apparatus. J Neurosci 28:8832–8843

    Article  CAS  PubMed  Google Scholar 

Download references


We would like to thank Kathleen Oram, Zachary Cohen, Erik Sklar, and Suzanne Meagher for excellent technical and administrative assistance. This work was supported by grants from HHMI, FRAXA, NIMH, NICHD, and the Simons Foundation.

Author information

Authors and Affiliations


Corresponding author

Correspondence to Mark F. Bear.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Krueger, D.D., Osterweil, E.K. & Bear, M.F. Activation of mGluR5 Induces Rapid and Long-Lasting Protein Kinase D Phosphorylation in Hippocampal Neurons. J Mol Neurosci 42, 1–8 (2010).

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI:


  • mGluR5
  • Protein kinase D
  • DHPG
  • MPEP
  • Hippocampus
  • Primary culture