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    L- and N-current but not M-current inhibition by M1 muscarinic receptors requires DAG lipase activity

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    Authors
    Liu, Liwang
    Heneghan, John F.
    Michael, Gregory J.
    Stanish, Lee F.
    Egertova, Michaela
    Rittenhouse, Ann R.
    Student Authors
    John Heneghan
    UMass Chan Affiliations
    Department of Physiology
    Document Type
    Journal Article
    Publication Date
    2008-02-06
    Keywords
    Animals; Arachidonic Acids; Calcium Channels, L-Type; Calcium Channels, N-Type; Cells, Cultured; Cyclohexanones; Humans; In Situ Hybridization; Lipoprotein Lipase; Muscarinic Agonists; Neurons; Oxotremorine; Patch-Clamp Techniques; Pertussis Toxin; Protease Inhibitors; Rats; Rats, Sprague-Dawley; Rats, Wistar; Receptor, Muscarinic M1; Recombinant Proteins; Superior Cervical Ganglion
    Life Sciences
    Medicine and Health Sciences
    Neuroscience and Neurobiology
    
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    Link to Full Text
    http://dx.doi.org/10.1002/jcp.21378
    Abstract
    Stimulation of postsynaptic M(1) muscarinic receptors (M(1)Rs) increases firing rates of both sympathetic and central neurons that underlie increases in vasomotor tone, heart rate, and cognitive memory functioning. At the cellular level, M(1)R stimulation modulates currents through various voltage-gated ion channels, including KCNQ K+ channels (M-current) and both L- and N-type Ca2+ channels (L- and N-current) by a pertussis toxin-insensitive, slow signaling pathway. Depletion of phosphatidylinositol-4,5-bisphosphate (PIP2) during M(1)R stimulation suffices to inhibit M-current. We found previously that following PIP2 hydrolysis by phospholipase C, activation of phospholipase A2 and liberation of a lipid metabolite, most likely arachidonic acid (AA) are necessary for L- and N-current modulation. Here we examined the involvement of a third lipase, diacylglycerol lipase (DAGL), in the slow pathway. We documented the presence of DAGL in superior cervical ganglion neurons, and then tested the highly selective DAGL inhibitor, RHC-80267, for its capacity to antagonize M(1)R-mediated modulation of whole-cell Ca2+ currents. RHC-80267 significantly reduced L- and N-current inhibition by the muscarinic agonist oxotremorine-M (Oxo-M) but did not affect their inhibition by exogenous AA. Moreover, voltage-dependent inhibition of N-current by Oxo-M remained in the presence of RHC-80267, indicating selective action on the slow pathway. RHC also blocked inhibition of recombinant N-current. In contrast, RHC-80267 had no effect on native M-current inhibition. These data are consistent with a role for DAGL in mediating L- and N-current inhibition. These results extend our previous findings that the signaling pathway mediating L- and N-current inhibition diverges from the pathway initiating M-current inhibition.
    Source
    J Cell Physiol. 2008 Jul;216(1):91-100. Link to article on publisher's site
    DOI
    10.1002/jcp.21378
    Permanent Link to this Item
    http://hdl.handle.net/20.500.14038/32889
    PubMed ID
    18247369
    Related Resources
    Link to Article in PubMed
    ae974a485f413a2113503eed53cd6c53
    10.1002/jcp.21378
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