Pituitary adenylate cyclase activating polypeptides (PACAP) are potent cardiovascular regulatory neuropeptides. We hypothesize that a critical site of PACAP action is within the peripheral parasympathetic cardiac ganglia that serve as local integrative centers. In guinea pig parasympathetic cardiac ganglia, all postganglionic neurons are innervated by PACAP-immunoreactive fibers, and PACAP peptides potently depolarize and increase excitability of the postganglionic cardiac neurons. The increase in membrane excitability of guinea pig cardiac parasympathetic neurons by PACAP is greater than that produced by any other neuropeptide studied to date, but mechanism(s) responsible for the PACAP-induced depolarization and increase in excitability are not known. The primary goal of the project is to establish the mechanisms underlying the PACAP-induced increase in excitability and depolarization of guinea pig cardiac neurons. The following specific aims are proposed.
Aim 1 : Establish the second messenger transduction cascades responsible for generation of the PACAP-induced increase in membrane excitability and depolarization.
Aim 2 : Establish the membrane ionic mechanisms underlying the PACAP-induced increase in membrane excitability.
Aim 3 : Establish the membrane ionic mechanisms generating the PACAP-induced inward current.
Aim 4 : Establish whether the PACAP-induced rise in intracellular calcium (Ca2+)i in cardiac neurons occurs from either Ca2+ influx or from Ca2+ release from IP3- or ryanodine-sensitive stores, and test whether the rise in (Ca2+)i is an initial step in the generation of the membrane depolarization or increased excitability. The results of these experiments will provide key, new insight into mechanisms determining PACAP-induced excitatory actions on neurons in the parasympathetic cardiac ganglia; ganglia that determine the extent of parasympathetic inhibitory drive on cardiac function.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL065481-01A2
Application #
6430160
Study Section
Special Emphasis Panel (ZRG1-MDCN-4 (01))
Program Officer
Lathrop, David A
Project Start
2001-12-06
Project End
2005-11-30
Budget Start
2001-12-06
Budget End
2002-11-30
Support Year
1
Fiscal Year
2002
Total Cost
$289,279
Indirect Cost
Name
University of Vermont & St Agric College
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
066811191
City
Burlington
State
VT
Country
United States
Zip Code
05405
Hoover, Donald B; Tompkins, John D; Parsons, Rodney L (2009) Differential activation of guinea pig intrinsic cardiac neurons by the PAC1 agonists maxadilan and pituitary adenylate cyclase-activating polypeptide 27 (PACAP27). J Pharmacol Exp Ther 331:197-203
Tompkins, John D; Parsons, Rodney L (2008) Identification of intracellular signaling cascades mediating the PACAP-induced increase in guinea pig cardiac neuron excitability. J Mol Neurosci 36:292-8
Young, Beth A; Girard, Beatrice M; Parsons, Rodney L (2008) Neurturin suppresses injury-induced neuronal activating transcription factor 3 expression in cultured guinea pig cardiac ganglia. J Comp Neurol 508:795-805
Girard, B M; Young, B A; Buttolph, T R et al. (2007) Regulation of neuronal pituitary adenylate cyclase-activating polypeptide expression during culture of guinea-pig cardiac ganglia. Neuroscience 146:584-93
Tompkins, John D; Ardell, Jeffrey L; Hoover, Donald B et al. (2007) Neurally released pituitary adenylate cyclase-activating polypeptide enhances guinea pig intrinsic cardiac neurone excitability. J Physiol 582:87-93
Hardwick, Jean C; Tompkins, John D; Locknar, Sarah A et al. (2006) Calcium influx through channels other than voltage-dependent calcium channels is critical to the pituitary adenylate cyclase-activating polypeptide-induced increase in excitability in guinea pig cardiac neurons. Ann N Y Acad Sci 1070:317-21
Girard, Beatrice M; Young, Beth A; Buttolph, Thomas R et al. (2006) Modulation of pituitary adenylate cyclase-activating polypeptide (PACAP) expression in explant-cultured guinea pig cardiac neurons. Ann N Y Acad Sci 1070:298-302
Parsons, Rodney L; Locknar, Sarah A; Young, Beth A et al. (2006) Presence and co-localization of vasoactive intestinal polypeptide with neuronal nitric oxide synthase in cells and nerve fibers within guinea pig intrinsic cardiac ganglia and cardiac tissue. Cell Tissue Res 323:197-209
Tompkins, John D; Hardwick, Jean C; Locknar, Sarah A et al. (2006) Ca2+ influx, but not Ca2+ release from internal stores, is required for the PACAP-induced increase in excitability in guinea pig intracardiac neurons. J Neurophysiol 95:2134-42
Hoover, Donald B; Ganote, Charles E; Ferguson, Shawn M et al. (2004) Localization of cholinergic innervation in guinea pig heart by immunohistochemistry for high-affinity choline transporters. Cardiovasc Res 62:112-21

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