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
DOI:
10.1523/JNEUROSCI.2102-06.2006
Language:
English
Publisher:
Society for Neuroscience
Publication Date:
2006
detail.hit.zdb_id:
1475274-8
detail.hit.zdb_id:
604637-X
SSG:
12
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