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Pituitary Adenylate Cyclase-Activating Polypeptide (PACAP) Alters Parasympathetic Neuron Gene Expression in a Time-dependent Fashion

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Abstract

Neuropeptides, including pituitary adenylate cyclase-activating polypeptide (PACAP), can influence diverse cellular processes over a broad temporal range. In ciliary ganglion (CG) neurons, for example, PACAP binding to high-affinity PAC1 receptors triggers transduction cascades that both rapidly modulate nicotinic receptors and synapses and support long-term survival. Since PACAP/PAC1 signaling recruits intracellular messengers and effectors that potently alter transcription, we examined its activation of the transcription factor CREB and then tested for changes in gene expression. PACAP/PAC1 signaling rapidly induced prolonged CREB activation in CG neurons by a phospholipase C -independent mechanism supported by Ca2+-influx, adenylate cyclase, and effectors, including protein kinase C (PKC) and possibly PKA. Since PACAP is abundant in the CG and released from depolarized presynaptic terminals, it is well suited to regulate gene expression relevant to neuronal and synaptic development. Gene array screens conducted using RNA from CG cultures grown with PACAP for 1/4, 24, or 96 h revealed a time-dependent pattern of >600 regulated transcripts, including several encoding proteins implicated in synaptic function, neuronal survival, and development. The results underscore rapid, neuromodulatory, and long-term, neurotrophic consequences of PAC1 signaling in CG neurons and suggest that PACAP exerts such diverse influences by altering the expression of specific gene transcripts in a time-dependent fashion.

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Acknowledgements

Support was provided by NIH grants R01-DA015536 and R21-DA022280 to JFM. We thank Dr. Gail Adams for technical assistance, and Drs. Marthe Howard and Phyllis Pugh for helpful comments on the work and manuscript.

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  1. Department of Neurosciences, University of Toledo College of Medicine, Block HS 108, 3000 Arlington Ave., Stop #1007, Toledo, OH, 43614-5804, USA

    Adriane D. Sumner & Joseph F. Margiotta

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  1. Adriane D. Sumner
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Correspondence to Joseph F. Margiotta.

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Supplementary Table 1

Parasympathetic neuron transcripts regulated by PACAP treatment. The fold increase or decrease in transcripts produced by each of the indicated PACAP treatments is depicted with values of ≥1.50 or ≤−1.50, respectively. For simplicity, transcripts from treatments that were at levels not significantly different those in untreated controls (p > 0.05) are listed with a value of 1. Asterisks (*) depict cases where PACAP up- or down-regulated the indicated transcript by more than 3-fold (see Table 2).(DOC 1.3 MB)

Supplementary Figure 1

PACAP regulates gene expression relevant to a range of cellular functions. Pie chart depicts up- or down-regulated CG neuronal transcripts assigned to 12 functional categories. Wedge areas represent the percent representation within each category relative to all regulated transcripts (N = 672).(PDF 40 KB)

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Sumner, A.D., Margiotta, J.F. Pituitary Adenylate Cyclase-Activating Polypeptide (PACAP) Alters Parasympathetic Neuron Gene Expression in a Time-dependent Fashion. J Mol Neurosci 36, 141–156 (2008). https://doi.org/10.1007/s12031-008-9103-5

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