cPLA2α-/- sympathetic neurons exhibit increased membrane excitability and loss of N-Type Ca2+ current inhibition by M1 muscarinic receptor signaling
Autor: | Liwang Liu, Ann R. Rittenhouse, Joseph V. Bonventre |
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Rok vydání: | 2018 |
Předmět: |
0301 basic medicine
Superior cervical ganglion Sympathetic Nervous System Hydrolases Physiology Cell Membranes Action Potentials Phospholipase Biochemistry Membrane Potentials Rats Sprague-Dawley chemistry.chemical_compound Calcium Channels N-Type Cell Signaling Animal Cells Muscarinic acetylcholine receptor Medicine and Health Sciences Phospholipids Neurons Multidisciplinary biology Esterases Brain Lipids Cell biology Enzymes Electrophysiology Laboratory Equipment Phospholipases Medicine Engineering and Technology Cellular Types Cellular Structures and Organelles Anatomy medicine.drug Research Article Signal Transduction Signal Inhibition Science Prefrontal Cortex Neurophysiology Equipment Muscarinic agonist Membrane Potential 03 medical and health sciences Phospholipase A2 Oxotremorine medicine Reaction Time Animals Phosphatidylinositol Calcium Signaling Phospholipase C Pipettes Group IV Phospholipases A2 Receptor Muscarinic M1 Biology and Life Sciences Proteins Cell Biology Rats 030104 developmental biology chemistry Cellular Neuroscience biology.protein Enzymology Calcium Neuroscience |
Zdroj: | PLoS ONE PLoS ONE, Vol 13, Iss 12, p e0201322 (2018) |
ISSN: | 1932-6203 |
Popis: | Group IVa cytosolic phospholipase A2 (cPLA2α) 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 cPLA2α’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 cPLA2α antagonists or dialyzing cPLA2α 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 cPLA2α-/- mice exhibited little N-current inhibition by Oxo-M, confirming a role for cPLA2α. In contrast, cPLA2α antibodies or the absence of cPLA2α 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 cPLA2α acts locally to metabolize PIP2 intimately associated with N- but not M-channels. To determine cPLA2α’s functional importance more globally, we examined action potential firing of cPLA2α+/+ and cPLA2α-/- SCG neurons, and found decreased latency to first firing and interspike interval resulting in a doubling of firing frequency in cPLA2α-/- neurons. These unanticipated findings identify cPLA2α as a tonic regulator of neuronal membrane excitability. |
Databáze: | OpenAIRE |
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