Department of Microbiology and Physiological Systems
Amino Acids, Peptides, and Proteins | Cells | Cellular and Molecular Physiology | Enzymes and Coenzymes | Nervous System | Neuroscience and Neurobiology
Group IVa cytosolic phospholipase A2 (cPLA2alpha) mediates GPCR-stimulated arachidonic acid (AA) release from phosphatidylinositol 4,5-bisphosphate (PIP2) located in plasma membranes. We previously found in superior cervical ganglion (SCG) neurons that PLA2 activity is required for voltage-independent N-type Ca2+ (N-) current inhibition by M1 muscarinic receptors (M1Rs). These findings are at odds with an alternative model, previously observed for M-current inhibition, where PIP2 dissociation from channels and subsequent metabolism by phospholipase C suffices for current inhibition. To resolve cPLA2alpha's importance, we have investigated its role in mediating voltage-independent N-current inhibition (~40%) that follows application of the muscarinic agonist oxotremorine-M (Oxo-M). Preincubation with different cPLA2alpha antagonists or dialyzing cPLA2alpha antibodies into cells minimized N-current inhibition by Oxo-M, whereas antibodies to Ca2+-independent PLA2 had no effect. Taking a genetic approach, we found that SCG neurons from cPLA2alpha-/- mice exhibited little N-current inhibition by Oxo-M, confirming a role for cPLA2alpha. In contrast, cPLA2alpha antibodies or the absence of cPLA2alpha had no effect on voltage-dependent N-current inhibition by M2/M4Rs or on M-current inhibition by M1Rs. These findings document divergent M1R signaling mediating M-current and voltage-independent N-current inhibition. Moreover, these differences suggest that cPLA2alpha acts locally to metabolize PIP2 intimately associated with N- but not M-channels. To determine cPLA2alpha's functional importance more globally, we examined action potential firing of cPLA2alpha+/+ and cPLA2alpha-/- SCG neurons, and found decreased latency to first firing and interspike interval resulting in a doubling of firing frequency in cPLA2alpha-/- neurons. These unanticipated findings identify cPLA2alpha as a tonic regulator of neuronal membrane excitability.
Neurons, Signal inhibition, Phospholipids, Phospholipases, Cell membranes, Prefrontal cortex, Action potentials, Pipettes
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Copyright: © 2018 Liu et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
DOI of Published Version
PLoS One. 2018 Dec 17;13(12):e0201322. doi: 10.1371/journal.pone.0201322. eCollection 2018. Link to article on publisher's site
Liu, Liwang; Bonventre, Joseph V.; and Rittenhouse, Ann R., "cPLA2alpha-/- sympathetic neurons exhibit increased membrane excitability and loss of N-Type Ca2+ current inhibition by M1 muscarinic receptor signaling" (2018). Open Access Articles. 3692.
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