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Presynaptically localized cyclic GMP-dependent protein kinase 1 is a key determinant of spinal synaptic potentiation and pain hypersensitivity
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نویسنده
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luo c. ,gangadharan v. ,bali k.k. ,xie r.-g. ,agarwal n. ,kurejova m. ,tappe-theodor a. ,tegeder i. ,feil s. ,lewin g. ,polgar e. ,todd a.j. ,schlossmann j. ,hofmann f. ,liu d.-l. ,hu s.-j. ,feil r. ,kuner t. ,kuner r.
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منبع
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plos biology - 2012 - دوره : 10 - شماره : 3
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چکیده
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Synaptic long-term potentiation (ltp) at spinal neurons directly communicating pain-specific inputs from the periphery to the brain has been proposed to serve as a trigger for pain hypersensitivity in pathological states. previous studies have functionally implicated the nmda receptor-no pathway and the downstream second messenger,cgmp,in these processes. because cgmp can broadly influence diverse ion-channels,kinases,and phosphodiesterases,pre- as well as post-synaptically,the precise identity of cgmp targets mediating spinal ltp,their mechanisms of action,and their locus in the spinal circuitry are still unclear. here,we found that protein kinase g1 (pkg-i) localized presynaptically in nociceptor terminals plays an essential role in the expression of spinal ltp. using the cre-lox p system,we generated nociceptor-specific knockout mice lacking pkg-i specifically in presynaptic terminals of nociceptors in the spinal cord,but not in post-synaptic neurons or elsewhere (sns-pkg-i -/- mice). patch clamp recordings showed that activity-induced ltp at identified synapses between nociceptors and spinal neurons projecting to the periaqueductal grey (pag) was completely abolished in sns-pkg-i -/- mice,although basal synaptic transmission was not affected. analyses of synaptic failure rates and paired-pulse ratios indicated a role for presynaptic pkg-i in regulating the probability of neurotransmitter release. inositol 1,4,5-triphosphate receptor 1 and myosin light chain kinase were recruited as key phosphorylation targets of presynaptic pkg-i in nociceptive neurons. finally,behavioural analyses in vivo showed marked defects in sns-pkg-i -/- mice in several models of activity-induced nociceptive hypersensitivity,and pharmacological studies identified a clear contribution of pkg-i expressed in spinal terminals of nociceptors. our results thus indicate that presynaptic mechanisms involving an increase in release probability from nociceptors are operational in the expression of synaptic ltp on spinal-pag projection neurons and that pkg-i localized in presynaptic nociceptor terminals plays an essential role in this process to regulate pain sensitivity. © 2012 luo et al.
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آدرس
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pharmacology institute,university of heidelberg,heidelberg,germany,institute of neuroscience,fourth military medical university,xi'an, China, pharmacology institute,university of heidelberg,heidelberg,germany,molecular medicine partnership unit of the european molecular biology,laboratory and the university of heidelberg medical faculty,heidelberg, Germany, pharmacology institute,university of heidelberg,heidelberg, Germany, institute of neuroscience,fourth military medical university,xi'an, China, pharmacology institute,university of heidelberg,heidelberg, Germany, pharmacology institute,university of heidelberg,heidelberg, Germany, pharmacology institute,university of heidelberg,heidelberg, Germany, pharmazentrum frankfurt,klinikum der johann wolfgang goethe universität,frankfurt am main, Germany, interfakultäres institut für biochemie,universität tübingen,tübingen, Germany, max delbrück center for molecular medicine,berlin-buch, Germany, spinal cord group,university of glasgow,west medical building,glasgow, United Kingdom, spinal cord group,university of glasgow,west medical building,glasgow, United Kingdom, for 923,institut für pharmakologie und toxikologie,technische universität münchen,munich,germany,institut fü r pharmakologie und toxikologie,universität regensburg,regensburg, Germany, for 923,institut für pharmakologie und toxikologie,technische universität münchen,munich, Germany, institute of neuroscience,fourth military medical university,xi'an, China, institute of neuroscience,fourth military medical university,xi'an, China, interfakultäres institut für biochemie,universität tübingen,tübingen, Germany, institute for anatomy and cell biology,university of heidelberg,heidelberg, Germany, pharmacology institute,university of heidelberg,heidelberg,germany,molecular medicine partnership unit of the european molecular biology,laboratory and the university of heidelberg medical faculty,heidelberg, Germany
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Authors
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