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L‐ and N‐current but not M‐current inhibition by M 1 muscarinic receptors requires DAG lipase activity
Author(s) -
Liu Liwang,
Heneghan John F.,
Michael Gregory J.,
Stanish Lee F.,
Egertová Michaela,
Rittenhouse Ann R.
Publication year - 2008
Publication title -
journal of cellular physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.529
H-Index - 174
eISSN - 1097-4652
pISSN - 0021-9541
DOI - 10.1002/jcp.21378
Subject(s) - oxotremorine , muscarinic acetylcholine receptor , pertussis toxin , chemistry , diacylglycerol lipase , endocrinology , stimulation , medicine , muscarinic agonist , agonist , biophysics , g protein , receptor , biochemistry , biology , cannabinoid receptor
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.