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The Journal of Neuroscience, November 8, 2006, 26(45):11588-11598; doi:10.1523/JNEUROSCI.2102-06.2006

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Cellular/Molecular
M₁ Muscarinic Receptors Inhibit L-type Ca²⁺ Current and M-Current by Divergent Signal Transduction Cascades

Liwang Liu,^1,2 Rubing Zhao,² Yan Bai,² Lee F. Stanish,² James E. Evans,³ Michael J. Sanderson,² Joseph V. Bonventre,⁴ and Ann R. Rittenhouse^1,2

¹Program in Neuroscience and Departments of ²Physiology and ³Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, Massachusetts 01655, and ⁴Harvard Institute of Medicine, Harvard Medical School and Brigham and Women's Hospital, Boston, Massachusetts 02115

Correspondence should be addressed to Dr. Ann R. Rittenhouse, Program of Neuroscience, Department of Physiology, University of Massachusetts Medical School, 55 Lake Avenue North, Worcester, MA 01655. Email: ann.rittenhouse{at}umassmed.edu

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, M₁-muscarinic receptors (M₁Rs) may inhibit both Ca²⁺ (L- and N-) and K⁺ (M-) currents by losing a putative interaction between channels and phosphatidylinositol-4,5-bisphosphate (PIP₂). However, we found previously that M₁R inhibition of N-current in superior cervical ganglion (SCG) neurons requires loss of PIP₂ and generation of a free fatty acid, probably arachidonic acid (AA) by phospholipase A₂ (PLA₂). It is not known whether PLA₂ activity and AA also participate in L- and M-current modulation in SCG neurons. To test whether PLA₂ plays a similar role in M₁R inhibition of L- and M-currents, we used several experimental approaches and found unanticipated divergent signaling. First, blocking resynthesis of PIP₂ minimized M-current recovery from inhibition, whereas L-current recovered normally. Second, L-current inhibition required group IVa PLA₂ [cytoplasmic PLA₂ (cPLA₂)], whereas M-current did not. Western blot and imaging studies confirmed acute activation of cPLA₂ by muscarinic stimulation. Third, in type IIa PLA₂ [secreted (sPLA₂)]^–/–/cPLA₂^–/– 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 M₁R-meditated channel modulation that broadens rather than restricts the roles of phospholipids and fatty acids in regulating ion channel activity.

Key words: arachidonic acid; calcium current; M₁ muscarinic; phosphatidylinositol-4,5-bisphosphate; PIP₂; phospholipase A₂; plasticity; superior cervical ganglion; sympathetic

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Received Dec. 24, 2005; revised Sept. 7, 2006; accepted Sept. 14, 2006.

Correspondence should be addressed to Dr. Ann R. Rittenhouse, Program of Neuroscience, Department of Physiology, University of Massachusetts Medical School, 55 Lake Avenue North, Worcester, MA 01655. Email: ann.rittenhouse{at}umassmed.edu

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