The cyclic AMP-activated sodium current in the molluscan neuron: A kinetic analysis of regulation by diffusion, phosphodiesterase and calcium ion
Huang, Rong-Chi
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Permalink
https://hdl.handle.net/2142/21576
Description
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
Issue Date
1989
Department of Study
Molecular and Integrative Physiology
Discipline
Physiology
Degree Granting Institution
University of Illinois at Urbana-Champaign
Degree Name
Ph.D.
Degree Level
Dissertation
Keyword(s)
Biology, Neuroscience
Biology, Animal Physiology
Language
eng
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.
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