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  • Rittenhouse, Ann R.  (3)
  • English  (3)
  • 1
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    L‐ and N‐current but not M‐current inhibition by M 1 muscarinic receptors requires DAG lipase activity
    Wiley ; 2008
    In:  Journal of Cellular Physiology Vol. 216, No. 1 ( 2008-07), p. 91-100
    Details
    In: Journal of Cellular Physiology, Wiley, Vol. 216, No. 1 ( 2008-07), p. 91-100
    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 Ca 2+ channels (L‐ and N‐current) by a pertussis toxin‐insensitive, slow signaling pathway. Depletion of phosphatidylinositol‐4,5‐bisphosphate (PIP 2 ) during M 1 R stimulation suffices to inhibit M‐current. We found previously that following PIP 2 hydrolysis by phospholipase C, activation of phospholipase A 2 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 Ca 2+ 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. J. Cell. Physiol. 216: 91–100, 2008. © 2008 Wiley‐Liss, Inc.
    Type of Medium: Online Resource
    ISSN: 0021-9541 , 1097-4652
    URL: Issue
    URL: Article
    DOI: 10.1002/jcp.v216:1
    DOI: 10.1002/jcp.21378
    Language: English
    Publisher: Wiley
    Publication Date: 2008
    detail.hit.zdb_id: 1478143-8
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  • 2
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    The Ca2+ channel β subunit determines whether stimulation of Gq-coupled receptors enhances or inhibits N current
    Rockefeller University Press ; 2009
    In:  Journal of General Physiology Vol. 134, No. 5 ( 2009-11-01), p. 369-384
    Details
    In: Journal of General Physiology, Rockefeller University Press, Vol. 134, No. 5 ( 2009-11-01), p. 369-384
    Abstract: In superior cervical ganglion (SCG) neurons, stimulation of M1 receptors (M1Rs) produces a distinct pattern of modulation of N-type calcium (N-) channel activity, enhancing currents elicited with negative test potentials and inhibiting currents elicited with positive test potentials. Exogenously applied arachidonic acid (AA) reproduces this profile of modulation, suggesting AA functions as a downstream messenger of M1Rs. In addition, techniques that diminish AA's concentration during M1R stimulation minimize N-current modulation. However, other studies suggest depletion of phosphatidylinositol-4,5-bisphosphate during M1R stimulation suffices to elicit modulation. In this study, we used an expression system to examine the physiological mechanisms regulating modulation. We found the β subunit (CaVβ) acts as a molecular switch regulating whether modulation results in enhancement or inhibition. In human embryonic kidney 293 cells, stimulation of M1Rs or neurokinin-1 receptors (NK-1Rs) inhibited activity of N channels formed by CaV2.2 and coexpressed with CaVβ1b, CaVβ3, or CaVβ4 but enhanced activity of N channels containing CaVβ2a. Exogenously applied AA produced the same pattern of modulation. Coexpression of CaVβ2a, CaVβ3, and CaVβ4 recapitulated the modulatory response previously seen in SCG neurons, implying heterogeneous association of CaVβ with CaV2.2. Further experiments with mutated, chimeric CaVβ subunits and free palmitic acid revealed that palmitoylation of CaVβ2a is essential for loss of inhibition. The data presented here fit a model in which CaVβ2a blocks inhibition, thus unmasking enhancement. Our discovery that the presence or absence of palmitoylated CaVβ2a toggles M1R- or NK-1R–mediated modulation of N current between enhancement and inhibition identifies a novel role for palmitoylation. Moreover, these findings predict that at synapses, modulation of N-channel activity by M1Rs or NK-1Rs will fluctuate between enhancement and inhibition based on the presence of palmitoylated CaVβ2a.
    Type of Medium: Online Resource
    ISSN: 1540-7748 , 0022-1295
    URL: Article
    DOI: 10.1085/jgp.200910203
    Language: English
    Publisher: Rockefeller University Press
    Publication Date: 2009
    detail.hit.zdb_id: 1477246-2
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  • 3
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    M 1 Muscarinic Receptors Inhibit L-type Ca 2+ Current and M-Current by Divergent Signal Transduction Cascades
    Society for Neuroscience ; 2006
    In:  The Journal of Neuroscience Vol. 26, No. 45 ( 2006-11-08), p. 11588-11598
    Details
    In: The Journal of Neuroscience, Society for Neuroscience, Vol. 26, No. 45 ( 2006-11-08), p. 11588-11598
    Abstract: Ion channels reside in a sea of phospholipids. During normal fluctuations in membrane potential and periods of modulation, lipids that directly associate with channel proteins influence gating by incompletely understood mechanisms. In one model, M 1 -muscarinic receptors (M 1 Rs) may inhibit both Ca 2+ (L- and N-) and K + (M-) currents by losing a putative interaction between channels and phosphatidylinositol-4,5-bisphosphate (PIP 2 ). However, we found previously that M 1 R inhibition of N-current in superior cervical ganglion (SCG) neurons requires loss of PIP 2 and generation of a free fatty acid, probably arachidonic acid (AA) by phospholipase A 2 (PLA 2 ). It is not known whether PLA 2 activity and AA also participate in L- and M-current modulation in SCG neurons. To test whether PLA 2 plays a similar role in M 1 R inhibition of L- and M-currents, we used several experimental approaches and found unanticipated divergent signaling. First, blocking resynthesis of PIP 2 minimized M-current recovery from inhibition, whereas L-current recovered normally. Second, L-current inhibition required group IVa PLA 2 [cytoplasmic PLA 2 (cPLA 2 )], whereas M-current did not. Western blot and imaging studies confirmed acute activation of cPLA 2 by muscarinic stimulation. Third, in type IIa PLA 2 [secreted ( sPLA 2 )] −/− / cPLA 2 −/− double-knock-out SCG neurons, muscarinic inhibition of L-current decreased. In contrast, M-current inhibition remained unaffected but recovery was impaired. Our results indicate that L-current is inhibited by a pathway previously shown to control M-current over-recovery after washout of muscarinic agonist. Our findings support a model of M 1 R-meditated channel modulation that broadens rather than restricts the roles of phospholipids and fatty acids in regulating ion channel activity.
    Type of Medium: Online Resource
    ISSN: 0270-6474 , 1529-2401
    URL: Article
    DOI: 10.1523/JNEUROSCI.2102-06.2006
    Language: English
    Publisher: Society for Neuroscience
    Publication Date: 2006
    detail.hit.zdb_id: 1475274-8
    SSG: 12
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