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M1 muscarinic receptors inhibit L-type Ca2+ current and M-current by divergent signal transduction cascades.

Authors: Liu, L  Zhao, R  Bai, Y  Stanish, LF  Evans, JE  Sanderson, MJ  Bonventre, JV  Rittenhouse, AR 
Citation: Liu L, etal., J Neurosci. 2006 Nov 8;26(45):11588-98.
Pubmed: (View Article at PubMed) PMID:17093080
DOI: Full-text: DOI:10.1523/JNEUROSCI.2102-06.2006

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.

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RGD Object Information
RGD ID: 1642449
Created: 2007-09-17
Species: All species
Last Modified: 2007-09-17
Status: ACTIVE



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RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.