Skip to main content
Log in

The Coffin-Lowry Syndrome-Associated Protein rsk2 and Neurosecretion

  • Report
  • Published:
Cellular and Molecular Neurobiology Aims and scope Submit manuscript

Abstract

Coffin-Lowry syndrome (CLS) is a syndromic form of X-linked mental retardation, characterized in male patients by psychomotor and growth retardation and various skeletal anomalies. CLS is caused by mutations in the RPS6KA3 gene, which encodes RSK2, a growth factor-regulated protein kinase. Cognitive deficiencies in CLS patients are prominent, but markedly variable in severity, even between siblings. However, the vast majority of patients are severely affected, with mental retardation ranging from moderate to profound. We used a RSK2-KO mouse model that shows no obvious brain abnormalities at the anatomical and histological levels to study the function of RSK2 in neurosecretion. Behavioral studies revealed normal motor coordination, but a profound retardation in spatial learning and a deficit in long-term spatial memory, providing evidence that RSK2 plays similar roles in mental functioning both in mice and human. We found that associative LTP at cortical inputs to the lateral amygdala was blocked in Rsk2 KO mice. Using an RNA interference rescue strategy in PC12 cells, we were able to demonstrate that RSK2 regulates catecholamine release through the phosphorylation of PLD. These results provide the first molecular evidence that RSK2 could regulate neurotransmitter release by activating PLD production of lipids required for exocytosis.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

References

  • Bader MF, Vitale N (2009) Phospholipase D in calcium-regulated exocytosis: lessons from chromaffin cells. Biochim Biophys Acta 1791:936–941

    CAS  PubMed  Google Scholar 

  • Bader MF, Holz RW, Kumakura K, Vitale N (2002) Exocytosis: the chromaffin cell as a model system. Ann NY Acad Sci 971:178–183

    Article  CAS  PubMed  Google Scholar 

  • Bader MF, Doussau F, Chasserot-Golaz S, Vitale N, Gasman S (2004) Coupling actin and membrane dynamics during calcium-regulated exocytosis: a role for Rho and ARF GTPases. Biochim Biophys Acta 1742:37–49

    Article  CAS  PubMed  Google Scholar 

  • Carriere A, Ray H, Blenis J, Roux PP (2008) The RSK factors of activating the Ras/MAPK signaling cascade. Front Biosci 13:4258–4275

    Article  CAS  PubMed  Google Scholar 

  • Fourcaudot E, Gambino F, Humeau Y, Casassus G, Shaban H, Poulain B, Lüthi A (2008) cAMP/PKA signaling and RIM1alpha mediate presynaptic LTP in the lateral amygdala. Proc Natl Acad Sci USA 105:15130–15135

    Article  CAS  PubMed  Google Scholar 

  • Fourcaudot E, Gambino F, Casassus G, Poulain B, Humeau Y, Lüthi A (2009) L-type voltage-dependent Ca(2+) channels mediate expression of presynaptic LTP in amygdala. Nat Neurosci 12:1093–1095

    Article  CAS  PubMed  Google Scholar 

  • Gambino F, Khelfaoui M, Poulain B, Bienvenu T, Chelly J, Humeau Y (2010) Synaptic maturation at cortical projections to the lateral amygdala in a mouse model of Rett syndrome. PLoS One 5:e11399

    Article  PubMed  Google Scholar 

  • Hauge C, Frodin M (2006) RSK, MSK in MAP kinase signalling. J Cell Sci 119:3021–3023

    Article  CAS  PubMed  Google Scholar 

  • Humeau Y, Vitale N, Chasserot-Golaz S, Dupont JL, Du G, Frohman MA, Bader MF, Poulain B (2001) A role for phospholipase D1 in neurotransmitter release. Proc Natl Acad Sci USA 98:15300–15305

    Article  CAS  PubMed  Google Scholar 

  • Humeau Y, Shaban H, Bissiere S, Lüthi A (2003) Presynaptic induction of heterosynaptic associative plasticity in the mammalian brain. Nature 426:841–845

    Article  CAS  PubMed  Google Scholar 

  • Humeau Y, Herry C, Kemp N, Shaban H, Fourcaudot E, Bissière S, Lüthi A (2005) Dendritic spine heterogeneity determines afferent-specific Hebbian plasticity in the amygdala. Neuron 45:119–131

    Article  CAS  PubMed  Google Scholar 

  • Humeau Y, Reisel D, Johnson AW, Borchardt T, Jensen V, Gebhardt C, Bosch V, Gass P, Bannerman DM, Good MA, Hvalby Ø, Sprengel R, Lüthi A (2007) A pathway-specific function for different AMPA receptor subunits in amygdala long-term potentiation and fear conditioning. J Neurosci 27:10947–10956

    Article  CAS  PubMed  Google Scholar 

  • Humeau Y, Gambino F, Chelly J, Vitale N (2009) X-linked mental retardation: focus on synaptic function and plasticity. J Neurochem 109:1–14

    Article  CAS  PubMed  Google Scholar 

  • Poirier R, Jacquot S, Vaillend C, Soutthiphong AA, Libbey M, Davis S, Laroche S, Hanauer A, Welzl H, Lipp HP, Wolfer DP (2007) Deletion of the Coffin-Lowry syndrome gene Rsk2 in mice is associated with impaired spatial learning and reduced control of exploratory behavior. Behav Genet 37:31–50

    Article  CAS  PubMed  Google Scholar 

  • Poteet-Smith CE, Smith JA, Lannigan DA, Freed TA, Sturgill TW (1999) Generation of constitutively active p90 ribosomal S6 kinase in vivo. Implications for the mitogen-activated protein kinase-activated protein kinase family. J Biol Chem 274:22135–22138

    Article  CAS  PubMed  Google Scholar 

  • Rettig J, Neher E (2002) Emerging roles of presynaptic proteins in calcium-triggered exocytosis. Science 298:781–785

    Article  CAS  PubMed  Google Scholar 

  • Schneggenburger R, Sakaba T, Neher E (2002) Vesicle pools and short-term synaptic depression: lessons from a large synapse. Trends Neurosci 25:206–212

    Article  CAS  PubMed  Google Scholar 

  • Shaban H, Humeau Y, Herry C, Cassasus G, Shigemoto R, Ciocchi S, Berbieri S, Van der Putten H, Kaupmann K, Bettler B, Lüthi A (2006) Generalization of amygdala LTP and conditioned fear in the absence of presynaptic inhibition. Nat Neurosci 9:1028–1035

    Article  CAS  PubMed  Google Scholar 

  • Stephenson JB, Hoffman MC, Russell AJ, Falconer J, Beach RC, Tolmie JL, McWilliam RC, Zuberi SM (2005) The movement disorders of Coffin-Lowry syndrome. Brain Dev 27:108–113

    Article  PubMed  Google Scholar 

  • Thomas GM, Rumbaugh GR, Harrar DB, Huganir RL (2005) Ribosomal S6 kinase 2 interacts with and phosphorylates PDZ domain-containing proteins and regulates AMPA receptor transmission. Proc Natl Acad Sci USA 102:15006–15011

    Article  CAS  PubMed  Google Scholar 

  • Trivier E, De Cesare D, Jacquot S, Pannetier S, Zackai E, Young I, Mandel JL, Sassone-Corsi P, Hanauer A (1996) Mutations in the kinase Rsk-2 associated with Coffin-Lowry syndrome. Nature 384:567–570

    Article  CAS  PubMed  Google Scholar 

  • Tsvetkov E, Carlezon WA, Benes FM, Kandel ER, Bolshakov VY (2002) Fear conditioning occludes LTP-induced presynaptic enhancement of synaptic transmission in the cortical pathway to the lateral amygdala. Neuron 34:289–300

    Article  CAS  PubMed  Google Scholar 

  • Vitale N, Caumont AS, Chasserot-Golaz S, Du G, Wu S, Sciorra VA, Morris AJ, Frohman MA, Bader MF (2001) Phospholipase D1: a key factor for the exocytotic machinery in neuroendocrine cells. EMBO J 20:2424–2434

    Article  CAS  PubMed  Google Scholar 

  • Zeniou M, Ding T, Trivier E, Hanauer A (2002) Expression analysis of RSK gene family members: the RSK2 gene, mutated in Coffin-Lowry syndrome, is prominently expressed in brain structures essential for cognitive function and learning. Hum Mol Genet 11:2929–2940

    Article  CAS  PubMed  Google Scholar 

  • Zeniou-Meyer M, Zabari N, Ashery U, Chasserot-Golaz S, Haeberle AM, Demais V, Bailly Y, Gottfried I, Nakanishi H, Neiman AM, Du G, Frohman MA, Bader MF, Vitale N (2007) Phospholipase D1 production of phosphatidic acid at the plasma membrane promotes exocytosis of large dense-core granules at a late stage. J. Biol. Chem. 282:21746–21757

    Article  CAS  PubMed  Google Scholar 

  • Zeniou-Meyer M, Liu Y, Béglé A, Olanish M, Hanauer A, Becherer U, Rettig J, Bader MF, Vitale N (2008) The Coffin-Lowry syndrome-associated protein RSK2 is implicated in calcium-regulated exocytosis through the regulation of PLD1. Proc Natl Acad Sci USA 105:8434–8439

    Article  CAS  PubMed  Google Scholar 

  • Zeniou-Meyer M, Béglé A, Bader MF, Vitale N (2009) The Coffin-Lowry syndrome-associated protein RSK2 controls neuroendocrine secretion through the regulation of phospholipase D1 at the exocytotic sites. Ann NY Acad Sci 1152:201–208

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

We wish to thank Dr André Hanauer for providing us with the RSK2 KO mice and Drs Jens Rettig and Ute Becherer for the capacitance recording of bovine chromaffin cells. We wish to thank Dr Nancy Grant for critical reading of the manuscript. This work was supported by ANR grants (ANR-09-BLAN-0264-01) to NV and (ANR-06-003-Neuro-01) to YH.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to N. Vitale.

Additional information

A commentary to this article can be found at doi:10.1007/s10571-010-9607-8.

Authors Humeau Y, Vitale N both contributed equally to this work.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Zeniou-Meyer, M., Gambino, F., Ammar, MR. et al. The Coffin-Lowry Syndrome-Associated Protein rsk2 and Neurosecretion. Cell Mol Neurobiol 30, 1401–1406 (2010). https://doi.org/10.1007/s10571-010-9578-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10571-010-9578-9

Keywords

Navigation