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
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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