title: Spinophilin-Targeted Protein Phosphatase-1 Alleviated Inflammatory Pain by Negative Control of MEK/ERK Signaling in Spinal Cord Dorsal Horn of Rats.
abstract: Protein phosphatase-1 (PP1), anchored by regulatory or targeting proteins at excitatory glutamatergic synapses, controls the phosphorylation of postsynaptic substrates and regulates the neurotransmission and plasticity. Here, we found that spinophilin, an actin-binding protein that targets PP1 at postsynaptic density, served as a scaffold for extracellular signal-regulated kinase (ERK) signaling components. Through the C-terminal PDZ domain, spinophilin directly interacted with ERK and its upstream mitogen-activated protein kinase kinase (MEK). PP1, recruited by spinophilin, gained access to and dephosphorylated these kinases, exerting a tonic inhibition of ERK signaling. The removal of PP1 inhibition by disturbing spinophilin/PP1 interaction allowed a restricted activation of MEK/ERK at synapses, which in turn augmented the synaptic transmission specifically mediated by GluN2B subunit-containing N-methyl-d-aspartate subtype of glutamate receptors. We provided evidence that in pain-related spinal cord dorsal horn, the scaffolding function of spinophilin played an important role in the negative control of ERK-dependent and GluN2B-dependent pain sensitization. Expression of wild-type spinophilin produced an effective analgesic action against chronic inflammatory pain induced by complete Freund's adjuvant in rats.
  
  
  CONCLUSIONS
  Extracellular signal-regulated kinase (ERK) relays the signals from multiple transmembrane receptors to a wide range of downstream effectors critical for the regulation of neuronal excitability and plasticity. The strength and duration of ERK signaling is spatiotemporally controlled by protein phosphatases. Sustained activation of ERK has been implicated in a variety of pathological processes. The current study revealed that spinophilin, a well characterized protein phosphatase 1 (PP1) synaptic targeting protein, was able to scaffold mitogen-activated protein kinase kinase (MEK) and ERK for dephosphorylation and inactivation by PP1. The loss of PP1 inhibition, as a result of spinophilin/PP1 dissociation, led to aberrant activation of MEK/ERK signaling, which had important implications for the exaggeration of NMDA receptor-dependent nociceptive synaptic transmission in spinal cord dorsal horn.
authors.affiliation: Department of Molecular Pharmacology, School of Pharmacy, Lanzhou University, Lanzhou, Gansu, China 730000 huxxiaodong@lzu.edu.cn.
authors.forename: Xiao-Dong
authors.initials: XD
authors.lastname: Hu
authors.affiliation: Department of Molecular Pharmacology, School of Pharmacy, Lanzhou University, Lanzhou, Gansu, China 730000.
authors.forename: Yan-Ni
authors.initials: YN
authors.lastname: Liu
authors.affiliation: Department of Molecular Pharmacology, School of Pharmacy, Lanzhou University, Lanzhou, Gansu, China 730000.
authors.forename: Zi-Yang
authors.initials: ZY
authors.lastname: Zhang
authors.affiliation: Department of Molecular Pharmacology, School of Pharmacy, Lanzhou University, Lanzhou, Gansu, China 730000.
authors.forename: Zheng-An
authors.initials: ZA
authors.lastname: Ma
authors.affiliation: Department of Molecular Pharmacology, School of Pharmacy, Lanzhou University, Lanzhou, Gansu, China 730000.
authors.forename: Zhan-Wei
authors.initials: ZW
authors.lastname: Suo
authors.affiliation: Department of Molecular Pharmacology, School of Pharmacy, Lanzhou University, Lanzhou, Gansu, China 730000.
authors.forename: Xian
authors.initials: X
authors.lastname: Yang
mesh_terms: D000818:Animals; D000697:Central Nervous System Stimulants / Q000494:pharmacology; D004195:Disease Models, Animal; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects; D005620:Freund's Adjuvant / Q000633:toxicity; D057809:HEK293 Cells; D006801:Humans; D066298:In Vitro Techniques; D007249:Inflammation / Q000139:chemically induced / Q000150:complications; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology*; D008297:Male; D008840:Microfilament Proteins / Q000235:genetics / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D010146:Pain / Q000188:drug therapy / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D010147:Pain Measurement; D018408:Patch-Clamp Techniques; D010852:Picrotoxin / Q000494:pharmacology; D054645:Protein Phosphatase 1 / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D066148:Spinal Cord Dorsal Horn / Q000378:metabolism*; D000099273:Neurabins
chemical_list: D000697:Central Nervous System Stimulants; D018691:Excitatory Amino Acid Antagonists; D005620:Freund's Adjuvant; D020930:MAP Kinase Kinase Kinases; D008840:Microfilament Proteins; D009419:Nerve Tissue Proteins; D010852:Picrotoxin; D054645:Protein Phosphatase 1; D016194:Receptors, N-Methyl-D-Aspartate; D000099273:Neurabins
keywords: NMDA receptor; extracellular signal-regulated kinase; pain; protein phosphatase-1; spinophilin