GSBS Student Publications

Title

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

Student Author(s)

John Heneghan

GSBS Program

Neuroscience

UMMS Affiliation

Department of Physiology

Date

2-6-2008

Document Type

Article

Medical Subject Headings

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

Disciplines

Life Sciences | Medicine and Health Sciences | Neuroscience and Neurobiology

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.

Rights and Permissions

Citation: J Cell Physiol. 2008 Jul;216(1):91-100. Link to article on publisher's site

Related Resources

Link to Article in PubMed

Journal Title

Journal of cellular physiology

PubMed ID

18247369