Cyclic AMP signaling contributes to neural plasticity and hyperexcitability in AH sensory neurons following intestinal Trichinella spiralis-induced inflammation.
Trichinella spiralis infection causes hyperexcitability in enteric after-hyperpolarising (AH) sensory neurons that is mimicked by neural, immune or inflammatory mediators known to stimulate adenylyl cyclase (AC)/cyclic 3',5'-adenosine monophosphate (cAMP) signaling. The hypothesis was tested that ongoing modulation and sustained amplification in the AC/cAMP/phosphorylated cAMP related element binding protrein (pCREB) signaling pathway contributes to hyperexcitability and neuronal plasticity in gut sensory neurons after nematode infection. Electrophysiological, immunological, molecular biological or immunochemical studies were done in T. spiralis-infected guinea-pigs (8000 larvae or saline) after acute-inflammation (7 days) or 35 days p.i., after intestinal clearance. Acute-inflammation caused AH-cell hyperexcitability and elevated mucosal and neural tissue levels of myeloperoxidase, mast cell tryptase, prostaglandin E2, leukotrine B4, lipid peroxidation, nitric oxide and gelatinase; lower level inflammation persisted 35 days p.i. Acute exposure to blockers of AC, histamine, cyclooxygenase or leukotriene pathways suppressed AH-cell hyperexcitability in a reversible manner. Basal cAMP responses or those evoked by forskolin (FSK), Ro-20-1724, histamine or substance P in isolated myenteric ganglia were augmented after T. spiralis infection; up-regulation also occurred in AC expression and AC-immunoreactivity in calbindin (AH) neurons. The cAMP-dependent slow excitatory synaptic transmission-like responses to histamine (mast cell mediator) or substance P (neurotransmitter) acting via G-protein coupled receptors (GPCR) in AH neurons were augmented by up to 2.5-fold after T. spiralis infection. FSK, histamine, substance P or T. spiralis acute infection caused a 5- to 30-fold increase in cAMP-dependent nuclear CREB phosphorylation in isolated ganglia or calbindin (AH) neurons. AC and CREB phosphorylation remained elevated 35 days p.i.. Ongoing immune activation, AC up-regulation, enhanced phosphodiesterase IV activity and facilitation of the GPCR-AC/cAMP/pCREB signaling pathway contributes to T. spiralis-induced neuronal plasticity and AH-cell hyperexcitability. This may be relevant in gut nematode infections and inflammatory bowel diseases, and is a potential therapeutic target.
Chen
Zhixiong
Z
Department of Anesthesiology, The Ohio State University, Columbus, OH 43210, USA.
Suntres
Zach
Z
Palmer
Jeffrey
J
Guzman
Jorge
J
Javed
Asad
A
Xue
Jianjing
J
Yu
Jun-Ge
JG
Cooke
Helen
H
Awad
Hamdy
H
Hassanain
Hamdy H
HH
Cardounel
Arturo J
AJ
Christofi
Fievos L
FL
D000818:Animals; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism*; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D016048:Dideoxyadenosine / Q000031:analogs & derivatives / Q000494:pharmacology; D015232:Dinoprostone / Q000378:metabolism; D006168:Guinea Pigs; D006632:Histamine / Q000494:pharmacology; D007093:Imidazoles / Q000494:pharmacology; D066298:In Vitro Techniques; D007413:Intestinal Mucosa / Q000187:drug effects / Q000294:innervation*; D007975:Leukotriene B4 / Q000378:metabolism; D008239:Lysine / Q000031:analogs & derivatives / Q000494:pharmacology; D008297:Male; D008564:Membrane Potentials / Q000502:physiology; D009130:Muscle, Smooth / Q000187:drug effects / Q000294:innervation; D009473:Neuronal Plasticity / Q000187:drug effects / Q000502:physiology*; D009475:Neurons, Afferent / Q000187:drug effects / Q000378:metabolism / Q000469:parasitology / Q000502:physiology*; D009569:Nitric Oxide / Q000378:metabolism; D009195:Peroxidase / Q000378:metabolism; D015398:Signal Transduction; D013373:Substance P / Q000494:pharmacology; D017392:Thiobarbituric Acid Reactive Substances / Q000378:metabolism; D017160:Trichinella spiralis / Q000378:metabolism / Q000502:physiology*; D014235:Trichinellosis / Q000378:metabolism* / Q000469:parasitology; D053802:Tryptases / Q000378:metabolism
D017362:Cyclic AMP Response Element-Binding Protein; D007093:Imidazoles; D017392:Thiobarbituric Acid Reactive Substances; C048819:4-(3,4-dibutoxybenzyl)-2-imidazolidinone; D005576:Colforsin; D007975:Leukotriene B4; D009569:Nitric Oxide; D013373:Substance P; D016048:Dideoxyadenosine; D006632:Histamine; C021008:2',5'-dideoxyadenosine; D000242:Cyclic AMP; D009195:Peroxidase; D053802:Tryptases; C013411:biocytin; D008239:Lysine; D015232:Dinoprostone