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Research ArticleArticle

Abelson Family Tyrosine Kinases Regulate the Function of Nicotinic Acetylcholine Receptors and Nicotinic Synapses on Autonomic Neurons

Selwyn S. Jayakar and Joseph F. Margiotta
Molecular Pharmacology July 2011, 80 (1) 97-109; DOI: https://doi.org/10.1124/mol.111.071308
Selwyn S. Jayakar
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Joseph F. Margiotta
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Abstract

Abelson family kinases (AFKs; Abl1, Abl2) are non-receptor tyrosine kinases (NRTKs) implicated in cancer, but they also have important physiological roles that include regulating synaptic structure and function. Recent studies using Abl-deficient mice and the antileukemia drug STI571 [imatinib mesylate (Gleevec); Novartis], which potently and selectively blocks Abl kinase activity, implicate AFKs in regulating presynaptic neurotransmitter release in hippocampus and postsynaptic clustering of nicotinic acetylcholine receptors (nAChRs) in muscle. Here, we tested whether AFKs are relevant for regulating nAChRs and nAChR-mediated synapses on autonomic neurons. AFK immunoreactivity was detected in ciliary ganglion (CG) lysates and neurons, and STI571 application blocked endogenous Abl tyrosine kinase activity. With similar potency, STI571 specifically reduced whole-cell current responses generated by both nicotinic receptor subtypes present on CG neurons (α3*- and α7-nAChRs) and lowered the frequency and amplitude of α3*-nAChR-mediated excitatory postsynaptic currents. Quantal analysis indicated that the synaptic perturbations were postsynaptic in origin, and confocal imaging experiments revealed they were unaccompanied by changes in nAChR clustering or alignment with presynaptic terminals. The results indicate that in autonomic neurons, Abl kinase activity normally supports postsynaptic nAChR function to sustain nAChR-mediated neurotransmission. Such consequences contrast with the influence of Abl kinase activity on presynaptic function and synaptic structure in hippocampus and muscle, respectively, demonstrating a cell-specific mechanism of action. Finally, because STI571 potently inhibits Abl kinase activity, the autonomic dysfunction side effects associated with its use as a chemotherapeutic agent may result from perturbed α3*- and/or α7-nAChR function.

Footnotes

  • ↵Embedded Image The online version of this article (available at http://molpharm.aspetjournals.org) contains supplemental material.

  • This work was supported by the National Institutes of Health National Institute on Drug Abuse [Grant R01-DA015536, R21-DA022280] (to J.F.M.); and by the National Science Foundation Division of Integrative Organismal Systems [Grant 0951549] (to J.F.M.).

  • Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org.

    doi:10.1124/mol.111.071308.

  • ABBREVIATIONS:

    nAChR
    nicotinic acetylcholine receptor
    α7-nAChR
    nAChR assembled from α7 subunits
    α3*-nAChR
    nAChR assembled from α3, β4, α5 ± β2 subunits
    AFK
    Abelson family tyrosine kinase
    Abl1
    c-Abl, Abelson family tyrosine kinase 1
    Abl2
    Arg, Abelson family tyrosine kinase 2
    CML
    chronic myeloid leukemia
    STI571
    imatinib mesylate
    MuSK
    muscle-specific kinase
    NRTK
    nonreceptor tyrosine kinase
    CG
    ciliary ganglion
    E
    embryonic day
    RS
    recording solution
    RShs
    recording solution supplemented with 10% heat-inactivated horse serum
    GTS-21
    3-(2,4-dimethoxybenzylidene)anabaseine
    αBgt
    α-bungarotoxin
    sEPSC
    spontaneous excitatory postsynaptic current
    eEPSC
    evoked excitatory postsynaptic current
    mEPSC
    miniature excitatory postsynaptic current
    TTX
    tetrodotoxin
    PBS
    phosphate-buffered saline
    BS/TX
    block solution containing PBS with 5% normal goat serum and 0.1% TX-100
    WS
    wash solution
    PDGF
    platelet-derived growth factor
    NGS
    normal goat serum
    BSA
    bovine serum albumin
    SV2
    synaptic vesicle protein 2
    ROI
    region of interest
    TB
    Tris-Triton buffer
    PAGE
    polyacrylamide gel electrophoresis
    mAb
    monoclonal antibody
    pAb
    polyclonal antibody
    HRP
    horseradish peroxidase
    AU
    arbitrary units
    PDGF
    platelet-derived growth factor
    PDGFR
    PDGF receptor
    SCF
    stem cell factor
    c-Kit
    stem cell factor receptor
    PSD
    postsynaptic density
    CRIPT
    cysteine rich PDZ binding protein
    PTPase
    protein-tyrosine phosphatase.

  • Received January 21, 2011.
  • Accepted April 18, 2011.
  • Copyright © 2011 The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 80 (1)
Molecular Pharmacology
Vol. 80, Issue 1
1 Jul 2011
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Research ArticleArticle

Abelson Family Tyrosine Kinases Regulate the Function of Nicotinic Acetylcholine Receptors and Nicotinic Synapses on Autonomic Neurons

Selwyn S. Jayakar and Joseph F. Margiotta
Molecular Pharmacology July 1, 2011, 80 (1) 97-109; DOI: https://doi.org/10.1124/mol.111.071308

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Research ArticleArticle

Abelson Family Tyrosine Kinases Regulate the Function of Nicotinic Acetylcholine Receptors and Nicotinic Synapses on Autonomic Neurons

Selwyn S. Jayakar and Joseph F. Margiotta
Molecular Pharmacology July 1, 2011, 80 (1) 97-109; DOI: https://doi.org/10.1124/mol.111.071308
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