Dual Role of Cyclic AMP-Dependent Protein Kinase in Neuritogenesis and Synaptogenesis during Neuronal Differentiation

Takuro Tojima, Suguru Kobayashi, Etsuro Ito

Research output: Contribution to journalArticle

53 Citations (Scopus)

Abstract

To create precise neural circuits in the nervous system, neuritogenesis and synaptogenesis are the critical cellular processes during neuronal differentiation. We examined the cyclic AMP (cAMP)-responsible signaling pathways for regulating neuritogenesis and synaptogenesis in NG108-15 cells. A rise in intracellular cAMP concentration by a membrane-permeable cAMP analog, dibutyryl cAMP (DBcAMP), led to an increase in the number of neurites and varicosities. Inhibition of cAMP-dependent protein kinase (PKA) activity by a PKA inhibitor (H89) accelerated this neuritogenesis and neurite outgrowth rate. Treatment with H89, however, decreased the number of varicosities and the frequency of postsynaptic miniature current recorded in the cultured cells, resulting in suppression of synaptogenesis. Immunoblot analyses revealed that PKA activity mediates phosphorylation of a gene transcription factor, cAMP-response element binding protein (CREB). On the other hand, inhibition of a mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) pathway by a MAPK/ERK kinase (MEK) inhibitor (PD98059) suppressed both neuritogenesis and neurite outgrowth without CREB phosphorylation. These results suggest strongly that PKA simultaneously plays two different roles in neuronal differentiation: inhibition of neuritogenesis and stimulation of synaptogenesis, via CREB-mediated gene expression.

Original languageEnglish
Pages (from-to)829-837
Number of pages9
JournalJournal of Neuroscience Research
Volume74
Issue number6
DOIs
Publication statusPublished - 2003 Dec 15
Externally publishedYes

Fingerprint

Cyclic AMP Response Element-Binding Protein
Cyclic AMP-Dependent Protein Kinases
Cyclic AMP
Extracellular Signal-Regulated MAP Kinases
Mitogen-Activated Protein Kinases
Protein Kinases
Phosphorylation
Synaptic Potentials
Bucladesine
Neurites
Protein Kinase Inhibitors
Nervous System
Cultured Cells
Transcription Factors
Phosphotransferases
Gene Expression
Membranes
Genes
N-(2-(4-bromocinnamylamino)ethyl)-5-isoquinolinesulfonamide
Neuronal Outgrowth

Keywords

  • CAMP-response element binding protein (CREB)
  • Mitogen-activated protein kinase (MAPK)
  • Neurite outgrowth
  • Postsynaptic miniature current
  • Varicosity

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Dual Role of Cyclic AMP-Dependent Protein Kinase in Neuritogenesis and Synaptogenesis during Neuronal Differentiation. / Tojima, Takuro; Kobayashi, Suguru; Ito, Etsuro.

In: Journal of Neuroscience Research, Vol. 74, No. 6, 15.12.2003, p. 829-837.

Research output: Contribution to journalArticle

@article{f59d53afcd1d4f9abbb2efbb9b8601d9,
title = "Dual Role of Cyclic AMP-Dependent Protein Kinase in Neuritogenesis and Synaptogenesis during Neuronal Differentiation",
abstract = "To create precise neural circuits in the nervous system, neuritogenesis and synaptogenesis are the critical cellular processes during neuronal differentiation. We examined the cyclic AMP (cAMP)-responsible signaling pathways for regulating neuritogenesis and synaptogenesis in NG108-15 cells. A rise in intracellular cAMP concentration by a membrane-permeable cAMP analog, dibutyryl cAMP (DBcAMP), led to an increase in the number of neurites and varicosities. Inhibition of cAMP-dependent protein kinase (PKA) activity by a PKA inhibitor (H89) accelerated this neuritogenesis and neurite outgrowth rate. Treatment with H89, however, decreased the number of varicosities and the frequency of postsynaptic miniature current recorded in the cultured cells, resulting in suppression of synaptogenesis. Immunoblot analyses revealed that PKA activity mediates phosphorylation of a gene transcription factor, cAMP-response element binding protein (CREB). On the other hand, inhibition of a mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) pathway by a MAPK/ERK kinase (MEK) inhibitor (PD98059) suppressed both neuritogenesis and neurite outgrowth without CREB phosphorylation. These results suggest strongly that PKA simultaneously plays two different roles in neuronal differentiation: inhibition of neuritogenesis and stimulation of synaptogenesis, via CREB-mediated gene expression.",
keywords = "CAMP-response element binding protein (CREB), Mitogen-activated protein kinase (MAPK), Neurite outgrowth, Postsynaptic miniature current, Varicosity",
author = "Takuro Tojima and Suguru Kobayashi and Etsuro Ito",
year = "2003",
month = "12",
day = "15",
doi = "10.1002/jnr.10754",
language = "English",
volume = "74",
pages = "829--837",
journal = "Journal of Neuroscience Research",
issn = "0360-4012",
publisher = "Wiley-Liss Inc.",
number = "6",

}

TY - JOUR

T1 - Dual Role of Cyclic AMP-Dependent Protein Kinase in Neuritogenesis and Synaptogenesis during Neuronal Differentiation

AU - Tojima, Takuro

AU - Kobayashi, Suguru

AU - Ito, Etsuro

PY - 2003/12/15

Y1 - 2003/12/15

N2 - To create precise neural circuits in the nervous system, neuritogenesis and synaptogenesis are the critical cellular processes during neuronal differentiation. We examined the cyclic AMP (cAMP)-responsible signaling pathways for regulating neuritogenesis and synaptogenesis in NG108-15 cells. A rise in intracellular cAMP concentration by a membrane-permeable cAMP analog, dibutyryl cAMP (DBcAMP), led to an increase in the number of neurites and varicosities. Inhibition of cAMP-dependent protein kinase (PKA) activity by a PKA inhibitor (H89) accelerated this neuritogenesis and neurite outgrowth rate. Treatment with H89, however, decreased the number of varicosities and the frequency of postsynaptic miniature current recorded in the cultured cells, resulting in suppression of synaptogenesis. Immunoblot analyses revealed that PKA activity mediates phosphorylation of a gene transcription factor, cAMP-response element binding protein (CREB). On the other hand, inhibition of a mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) pathway by a MAPK/ERK kinase (MEK) inhibitor (PD98059) suppressed both neuritogenesis and neurite outgrowth without CREB phosphorylation. These results suggest strongly that PKA simultaneously plays two different roles in neuronal differentiation: inhibition of neuritogenesis and stimulation of synaptogenesis, via CREB-mediated gene expression.

AB - To create precise neural circuits in the nervous system, neuritogenesis and synaptogenesis are the critical cellular processes during neuronal differentiation. We examined the cyclic AMP (cAMP)-responsible signaling pathways for regulating neuritogenesis and synaptogenesis in NG108-15 cells. A rise in intracellular cAMP concentration by a membrane-permeable cAMP analog, dibutyryl cAMP (DBcAMP), led to an increase in the number of neurites and varicosities. Inhibition of cAMP-dependent protein kinase (PKA) activity by a PKA inhibitor (H89) accelerated this neuritogenesis and neurite outgrowth rate. Treatment with H89, however, decreased the number of varicosities and the frequency of postsynaptic miniature current recorded in the cultured cells, resulting in suppression of synaptogenesis. Immunoblot analyses revealed that PKA activity mediates phosphorylation of a gene transcription factor, cAMP-response element binding protein (CREB). On the other hand, inhibition of a mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) pathway by a MAPK/ERK kinase (MEK) inhibitor (PD98059) suppressed both neuritogenesis and neurite outgrowth without CREB phosphorylation. These results suggest strongly that PKA simultaneously plays two different roles in neuronal differentiation: inhibition of neuritogenesis and stimulation of synaptogenesis, via CREB-mediated gene expression.

KW - CAMP-response element binding protein (CREB)

KW - Mitogen-activated protein kinase (MAPK)

KW - Neurite outgrowth

KW - Postsynaptic miniature current

KW - Varicosity

UR - http://www.scopus.com/inward/record.url?scp=0344118182&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0344118182&partnerID=8YFLogxK

U2 - 10.1002/jnr.10754

DO - 10.1002/jnr.10754

M3 - Article

C2 - 14648587

AN - SCOPUS:0344118182

VL - 74

SP - 829

EP - 837

JO - Journal of Neuroscience Research

JF - Journal of Neuroscience Research

SN - 0360-4012

IS - 6

ER -