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The cyclic AMP-activated sodium current in the molluscan neuron: A kinetic analysis of regulation by diffusion, phosphodiesterase and calcium ion

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Title: The cyclic AMP-activated sodium current in the molluscan neuron: A kinetic analysis of regulation by diffusion, phosphodiesterase and calcium ion
Author(s): Huang, Rong-Chi
Department / Program: Molecular and Integrative Physiology
Discipline: Physiology
Degree Granting Institution: University of Illinois at Urbana-Champaign
Degree: Ph.D.
Genre: Dissertation
Subject(s): Biology, Neuroscience Biology, Animal Physiology
Abstract: Effects of cyclic AMP on pedal neurons of the marine mollusc, Pleurobranchaea californica were studied by intracellular iontophoresis of cyclic AMP under voltage clamp condition. The I$\sb{\rm Na,cAMP}$ response to cyclic AMP injection is resistant to protein kinase inhibitors, and is very likely mediated by direct cyclic AMP binding to the channel receptor. The slow I$\sb{\rm Na,cAMP}$ is regulated by diffusion-hydrolysis kinetics: it varied in latency to current onset, latency to peak amplitude, and amplitude with the distance of the membrane to the tip of the iontophoretic cyclic AMP injection electrode; the phosphodiesterase inhibitor isobutylmethyxanthine (IBMX) in increasing concentrations motonically decreased the decay rates of the I$\sb{\rm Na,cAMP}$ response. A diffusion-reaction model incorporating terms for diffusion and degradation of cyclic AMP accurately fitted the time course of I$\sb{\rm Na,cAMP}$ response to a pulse of cyclic AMP. An application of the model allows extraction of phosphodiesterase activity as a first-order rate constant from the exponential decay phase of the I$\sb{\rm Na,cAMP}$ response.Intracellular Ca$\sp{2+}$ suppresses the I$\sb{\rm Na,cAMP}$ response; in contrast, serotonin, IBMX, and tonic injection of cyclic AMP tonically activate the I$\sb{\rm Na,cAMP}$ response and reduce its sensitivity to Ca$\sp{2+}$ modulation. The mutually antagonistic effects of intracellular Ca$\sp{2+}$ and cyclic AMP on the I$\sb{\rm Na,cAMP}$ response were best explained in terms of a competitive binding model: intracellular Ca$\sp{2+}$ suppresses I$\sb{\rm Na,cAMP}$ by decreasing the channel binding for cyclic AMP, and cyclic AMP decreases the channel affinity for intracellular Ca$\sp{2+}$. The competitive binding model also predicts supporting results of experiment tests.Extracellular Ca$\sp{2+}$ also regulates I$\sb{\rm Na,cAMP}$ by affecting cyclic AMP binding affinity in addition to its effect on channel conductance. Low extracellular Ca$\sp{2+}$ converts a low maximum amplitude/high cyclic AMP binding affinity current to a high maximum amplitude/low cyclic AMP binding affinity one; this design augments the intracellular Ca$\sp{2+}$ suppressive effect and thus serves as a safeguard preventing high cyclic AMP-induced pathological excitation. In conclusion, low extracellular Ca$\sp{2+}$ complements intracellular Ca$\sp{2+}$ in regulating I$\sb{\rm Na,cAMP}$ response.
Issue Date: 1989
Type: Text
Language: English
Rights Information: Copyright 1989 Huang, Rong-Chi
Date Available in IDEALS: 2011-05-07
Identifier in Online Catalog: AAI9010897
OCLC Identifier: (UMI)AAI9010897

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