Arachidonic acid mediates muscarinic inhibition and enhancement of N-type Ca2+ current in sympathetic neurons
Program in Neuroscience; Department of Physiology
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.
DOI of Published Version
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
Proceedings of the National Academy of Sciences of the United States of America
Liu, Liwang and Rittenhouse, Ann R., "Arachidonic acid mediates muscarinic inhibition and enhancement of N-type Ca2+ current in sympathetic neurons" (2002). Open Access Articles. 1774.