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M1Muscarinic Receptors Inhibit L-type Ca2+Current and M-Current by Divergent Signal Transduction Cascades
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| Zeitschriftentitel: | The Journal of Neuroscience |
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| Personen und Körperschaften: | , , , , , , , |
| In: | The Journal of Neuroscience, 26, 2006, 45, S. 11588-11598 |
| Format: | E-Article |
| Sprache: | Englisch |
| veröffentlicht: |
Society for Neuroscience
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| Schlagwörter: |
| Zusammenfassung: | <jats:p>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<jats:sub>1</jats:sub>-muscarinic receptors (M<jats:sub>1</jats:sub>Rs) may inhibit both Ca<jats:sup>2+</jats:sup>(L- and N-) and K<jats:sup>+</jats:sup>(M-) currents by losing a putative interaction between channels and phosphatidylinositol-4,5-bisphosphate (PIP<jats:sub>2</jats:sub>). However, we found previously that M<jats:sub>1</jats:sub>R inhibition of N-current in superior cervical ganglion (SCG) neurons requires loss of PIP<jats:sub>2</jats:sub>and generation of a free fatty acid, probably arachidonic acid (AA) by phospholipase A<jats:sub>2</jats:sub>(PLA<jats:sub>2</jats:sub>). It is not known whether PLA<jats:sub>2</jats:sub>activity and AA also participate in L- and M-current modulation in SCG neurons. To test whether PLA<jats:sub>2</jats:sub>plays a similar role in M<jats:sub>1</jats:sub>R inhibition of L- and M-currents, we used several experimental approaches and found unanticipated divergent signaling. First, blocking resynthesis of PIP<jats:sub>2</jats:sub>minimized M-current recovery from inhibition, whereas L-current recovered normally. Second, L-current inhibition required group IVa PLA<jats:sub>2</jats:sub>[cytoplasmic PLA<jats:sub>2</jats:sub>(cPLA<jats:sub>2</jats:sub>)], whereas M-current did not. Western blot and imaging studies confirmed acute activation of cPLA<jats:sub>2</jats:sub>by muscarinic stimulation. Third, in type IIa PLA<jats:sub>2</jats:sub>[secreted (<jats:italic>sPLA<jats:sub>2</jats:sub></jats:italic>)]<jats:sup>−/−</jats:sup>/<jats:italic>cPLA</jats:italic><jats:sub arrange="stagger"><jats:italic>2</jats:italic></jats:sub><jats:sup arrange="stagger">−/−</jats:sup>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<jats:sub>1</jats:sub>R-meditated channel modulation that broadens rather than restricts the roles of phospholipids and fatty acids in regulating ion channel activity.</jats:p> |
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| Umfang: | 11588-11598 |
| ISSN: |
0270-6474
1529-2401 |
| DOI: | 10.1523/jneurosci.2102-06.2006 |