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

AUTOR(ES)

Liu, Liwang

FONTE

The National Academy of Sciences

RESUMO

N-type Ca2+ channels participate in acute activity-dependent processes such as regulation of Ca2+-activated K+ channels and in more prolonged events such as gene transcription and long-term depression. A slow postsynaptic M1 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 Ca2+-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 Ca2+ current in either neuronal or nonneuronal cells, we nevertheless tested whether a fatty acid signaling cascade was involved. Blocking phospholipase C, phospholipase A2, 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 Gq was also confirmed by blocking muscarinic modulation of Ca2+ currents with anti-Gqα antibody. Our finding that AA participates in the slow pathway strongly suggests that it may be the previously unknown diffusible second messenger.

Documentos Relacionados

• Functional dependence of Ca(2+)-activated K+ current on L- and N-type Ca2+ channels: differences between chicken sympathetic and parasympathetic neurons suggest different regulatory mechanisms.
• Tumour necrosis factor α activates nuclear factor κB signalling to reduce N-type voltage-gated Ca2+ current in postganglionic sympathetic neurons
• Effect of G protein heterotrimer composition on coupling of neurotransmitter receptors to N-type Ca2+ channel modulation in sympathetic neurons
• Intracellular Ca2+ buffers disrupt muscarinic suppression of Ca2+ current and M current in rat sympathetic neurons.
• Characterization of muscarinic receptor subtypes inhibiting Ca2+ current and M current in rat sympathetic neurons.