Activity-dependent transcriptional activation and PACAP

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J Biol Chem. 2004 Sep 7 [Epub ahead of print]

Activity-dependent transcriptional activation and mRNA stabilization for

cumulative expression of PACAP mRNA controlled by calcium and cAMP signals

in neurons.

Fukuchi M, Tabuchi A, Tsuda M.

Department of Biological Chemistry, Toyama Medical and Pharmaceutical

University, Toyama, Toyama 930-0194.

Although it has been established that an activity-dependent gene

transcription is induced by the calcium (Ca(2+)) signals in neurons, it is

unclear how the specific mRNA moieties are transiently accumulated in

response to synaptic transmission which evokes multiple intracellular

signals including Ca(2+) and cAMP ones.

The expression of pituitary adenylate cyclase activating polypeptide

(PACAP), a neuropeptide, is controlled by Ca(2+) signals evoked via membrane

depolarization in neurons, and, in cultured rat cortical neuronal cells, we

found that the Ca(2+) signal-mediated activation of the PACAP gene promoter

was critically controlled by a single cAMP-response element (CRE) located at

around 200, to which the CRE-binding protein (CREB) predominantly bound. The

Ca(2+) signal-induced expression of PACAP mRNA was enhanced by forskolin,

which evokes cAMP signals.

In support, the PACAP gene promoter was synergistically enhanced by Ca(2+)

and cAMP signals through the CRE, accompanying a prolonged activation of

extracellular signal-related protein kinase 1/2 (ERK1/2) and CREB. On the

other hand, sole administration of forskolin markedly reduced the cellular

content of PACAP mRNA, which was restored by addition of Ca(2+) signals.

We found that the stability of PACAP mRNA was increased in response to

Ca(2+) signals, but not that of activity-regulated cytoskeleton-associated

protein (Arc) mRNA, indicating an activity-dependent stabilization of

specific mRNA species in neurons, which can antagonize the regulation

mediated by cAMP signals.

Thus, the transcriptional activation and mRNA stabilization are coordinately

regulated by Ca(2+) and cAMP signals for the cumulative expression of PACAP

mRNA in neurons.

PMID: 15355970 [PubMed - as supplied by publisher]

J Mol Neurosci. 2004;24(2):181-8. Related Articles, Links

Brain injury-dependent expression of activity-dependent neuroprotective

protein.

Zaltzman R, androvich A, Beni SM, Trembovler V, Shohami E, Gozes I.

Department of Clinical Biochemistry, Sackler Medical School, Tel Aviv

University, Tel Aviv 69978, Israel.

Activity-dependent neuroprotective protein (ADNP), a crucial brain

development factor, contains a unique sequence, termed NAPVSIPQ, which

protects mice against closed head injury (CHI). The aim of this study was to

determine whether CHI affects ADNP mRNA expression in the injured brain

hemisphere. Male C57JBL/6J mice were subjected to CHI. Brains were removed 5

h, 24 h, 7 d, and 29 d post-CHI. A comparison was made between ADNP mRNA in

the injured versus the noninjured hemisphere using real-time polymerase

chain reaction. A nonsignificant change (p > 0.05) was found 5 h, 24 h, and

7 d post-CHI. However, a significant increase (p < 0.05) in ADNP mRNA

expression was detected in the injured cerebral hemisphere 29 d post-CHI.

The data presented may be associated with ADNP's crucial involvement in

brain development and response to injury.

PMID: 15456931 [PubMed - in process]

The discovery of protective peptides described herein has its basis in the

neurotrophic and growth-promoting properties of VIP. Although VIP apparently

has fundamental roles in the regulation of embryo/brain development

(Gressens et al., 1993), the peptide itself is quickly degraded on systemic

administration, making it a poor therapeutic agent. In contrast, several

pharmacological properties of NAP and ADNF-9 form the basis of their unique

therapeutic potential: potency at femtomolar concentrations and apparent

stability in vivo, particularly in the case of NAP. Recovery of significant

amounts of radioactive material comigrating with intact NAP in embryos 60

min after systemic administration attests to the stability of this peptide.

These studies, in addition to providing a potential important agent for the

study of alcohol-induced damage/death, suggest a promising approach to the

treatment of human neurodegenerative disease that involve oxidative stress

and/or dysregulation of apoptosis.

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