Arachidonic acid mediates muscarinic inhibition and enhancement of N-type Ca2+ current in sympathetic neurons

UMMS Affiliation

Program in Neuroscience; Department of Physiology



Document Type



Animals; Animals, Newborn; Arachidonic Acid; Calcium Channel Blockers; Calcium Channels, N-Type; Membrane Potentials; Muscarinic Antagonists; Neurons; Nimodipine; Oxotremorine; Rats; Rats, Sprague-Dawley; Receptor, Muscarinic M1; Receptors, Muscarinic; Superior Cervical Ganglion


Life Sciences | Medicine and Health Sciences


N-type Ca(2+) channels participate in acute activity-dependent processes such as regulation of Ca(2+)-activated K(+) channels and in more prolonged events such as gene transcription and long-term depression. A slow postsynaptic M(1) muscarinic receptor-mediated modulation of N-type current in superior cervical ganglion neurons may be important in regulating these processes. This slow pathway inhibits N-type current by using a diffusible second messenger that has remained unidentified for more than a decade. Using whole-cell patch-clamp techniques, which isolate the slow pathway, we found that the muscarinic agonist oxotremorine methiodide not only inhibits currents at positive potentials but enhances N-type current at negative potentials. Enhancement was also observed in cell-attached patches. These findings provide evidence for N-type Ca(2+)-current enhancement by a classical neurotransmitter. Moreover, enhancement and inhibition of current by oxotremorine methiodide mimics modulation observed with direct application of a low concentration of arachidonic acid (AA). Although no transmitter has been reported to use AA as a second messenger to modulate any Ca(2+) current in either neuronal or nonneuronal cells, we nevertheless tested whether a fatty acid signaling cascade was involved. Blocking phospholipase C, phospholipase A(2), or AA but not AA metabolism minimized muscarinic modulation of N-type current, supporting the participation of these molecules in the slow pathway. A role for the G protein G(q) was also confirmed by blocking muscarinic modulation of Ca(2+) currents with anti-G(qalpha) antibody. Our finding that AA participates in the slow pathway strongly suggests that it may be the previously unknown diffusible second messenger.

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Citation: Proc Natl Acad Sci U S A. 2003 Jan 7;100(1):295-300. Epub 2002 Dec 20. Link to article on publisher's site

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Journal Title

Proceedings of the National Academy of Sciences of the United States of America

PubMed ID