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Multiple Mechanisms Contribute to the PAC1 Modulation of Parasympathetic Cardiac Neuron Excitability

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Pituitary Adenylate Cyclase Activating Polypeptide — PACAP

Part of the book series: Current Topics in Neurotoxicity ((Current Topics Neurotoxicity,volume 11))

Abstract

Pituitary adenylate cyclase-activating polypeptide (PACAP) is a potent intercellular signaling molecule that regulates a variety of central and peripheral neuronal circuits important for behavior and physiological homeostasis. Although central neurons are not readily accessible for mechanistic studies, the ability for PACAP/PAC1 receptor signaling to increase neuronal excitability in guinea pig parasympathetic cardiac ganglia provides a unique means to establish intracellular PACAP mechanisms in neuronal function. The guinea pig cardiac neurons predominantly express a very short null PAC1 receptor isoform which is coupled to the adenylyl cyclase and MEK/ERK signaling cascades. PACAP/PAC1 receptor activation of adenylyl cyclase and the resulting rise in intracellular cAMP enhances the nonselective cationic current I h; treatment with I h inhibitors diminishes the PACAP-induced increase in excitability. Thus, a shift in the voltage-dependence of I h activation is one ionic mechanism contributing to the PACAP-induced increase in cardiac neuron excitability. Low concentrations of nickel also blunt the peptide-induced increase in excitability, suggesting that a PACAP enhanced calcium influx through T-type voltage-dependent calcium channels contributes to the modulation of excitability. Reducing ambient temperature and treatments with endocytosis inhibitors Pitstop2 or dynasore efficaciously block PACAP modulation of excitability suggesting PACAP/PAC1 receptor internalization for endosomal MEK/ERK activation is requisite for the PACAP responses. In sum, the results presented in this review demonstrate that the PACAP/PAC1 receptor interactions can activate multiple intracellular signaling cascades to selectively modulate ionic conductances that gate neuronal excitability.

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Acknowledgements

The authors thank Ms. Sandra Bossick for her assistance in preparation of this chapter for publication. Studies from the Parsons’ laboratory described in this chapter were supported in part by NIH grants NS 23978, HL 65481, P20 RR16435, and P30 GM103498/P30 RR032135.

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Authors and Affiliations

  1. Department of Neurological Sciences, University of Vermont College of Medicine, 89 Beaumont Avenue, C427 Given, Burlington, VT, 05405, USA

    Rodney L. Parsons, Laura A. Merriam, Beatrice M. Girard & Victor May

  2. Department of Medicine (Cardiology), David Geffen School of Medicine, University of California, Los Angeles, CA, 90095, USA

    John D. Tompkins

  3. Department of Biology, Ithaca College, Ithaca, NY, 14850, USA

    Jean C. Hardwick

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  1. Rodney L. Parsons
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Correspondence to Rodney L. Parsons .

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Editors and Affiliations

  1. Department of Anatomy MTA-PTE “Lendulet” PACAP Research Team, University of Pecs, Pecs, Hungary

    Dora Reglodi

  2. Department of Anatomy MTA-PTE “Lendulet” PACAP Research Team, University of Pecs, Pecs, Hungary

    Andrea Tamas

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Parsons, R.L., Tompkins, J.D., Hardwick, J.C., Merriam, L.A., Girard, B.M., May, V. (2016). Multiple Mechanisms Contribute to the PAC1 Modulation of Parasympathetic Cardiac Neuron Excitability. In: Reglodi, D., Tamas, A. (eds) Pituitary Adenylate Cyclase Activating Polypeptide — PACAP. Current Topics in Neurotoxicity, vol 11. Springer, Cham. https://doi.org/10.1007/978-3-319-35135-3_13

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