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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
URI:http://hdl.handle.net/2142/21576
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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