title: ERK2 Alone Drives Inflammatory Pain But Cooperates with ERK1 in Sensory Neuron Survival.
abstract: Extracellular signal-regulated kinases 1 and 2 (ERK1/2) are highly homologous yet distinct components of signal transduction pathways known to regulate cell survival and function. Recent evidence indicates an isoform-specific role for ERK2 in pain processing and peripheral sensitization. However, the function of ERK2 in primary sensory neurons has not been directly tested. To dissect the isoform-specific function of ERK2 in sensory neurons, we used mice with Cre-loxP-mediated deletion of ERK2 in Nav1.8(+) sensory neurons that are predominantly nociceptors. We find that ERK2, unlike ERK1, is required for peripheral sensitization and cold sensation. We also demonstrate that ERK2, but not ERK1, is required to preserve epidermal innervation in a subset of peptidergic neurons. Additionally, deletion of both ERK isoforms in Nav1.8(+) sensory neurons leads to neuron loss not observed with deletion of either isoform alone, demonstrating functional redundancy in the maintenance of sensory neuron survival. Thus, ERK1 and ERK2 exhibit both functionally distinct and redundant roles in sensory neurons.
  
  
  CONCLUSIONS
  ERK1/2 signaling affects sensory neuron function and survival. However, it was not clear whether ERK isoform-specific roles exist in these processes postnatally. Previous work from our laboratory suggested either functional redundancy of ERK isoforms or a predominant role for ERK2 in pain; however, the tools to discriminate between these possibilities were not available at the time. In the present study, we use new genetic knock-out lines to demonstrate that ERK2 in sensory neurons is necessary for development of inflammatory pain and for postnatal maintenance of peptidergic epidermal innervation. Interestingly, postnatal loss of both ERK isoforms leads to a profound loss of sensory neurons. Therefore, ERK1 and ERK2 display both functionally distinct and redundant roles in sensory neurons.
authors.affiliation: Washington University Pain Center, Department of Anesthesiology, St. Louis, Missouri 63110, and.
authors.forename: Daniel E
authors.initials: DE
authors.lastname: O'Brien
authors.affiliation: Washington University Pain Center, Department of Anesthesiology, St. Louis, Missouri 63110, and.
authors.forename: Benedict J
authors.identifier: http://orcid.org/0000-0002-0171-3411
authors.initials: BJ
authors.lastname: Alter
authors.affiliation: Washington University Pain Center, Department of Anesthesiology, St. Louis, Missouri 63110, and.
authors.forename: Maiko
authors.initials: M
authors.lastname: Satomoto
authors.affiliation: Washington University Pain Center, Department of Anesthesiology, St. Louis, Missouri 63110, and.
authors.forename: Clinton D
authors.initials: CD
authors.lastname: Morgan
authors.affiliation: Washington University Pain Center, Department of Anesthesiology, St. Louis, Missouri 63110, and.
authors.forename: Steve
authors.initials: S
authors.lastname: Davidson
authors.affiliation: Washington University Pain Center, Department of Anesthesiology, St. Louis, Missouri 63110, and.
authors.forename: Sherri K
authors.initials: SK
authors.lastname: Vogt
authors.affiliation: Washington University Pain Center, Department of Anesthesiology, St. Louis, Missouri 63110, and.
authors.forename: Megan E
authors.identifier: http://orcid.org/0000-0002-0105-150X
authors.initials: ME
authors.lastname: Norman
authors.affiliation: Washington University Pain Center, Department of Anesthesiology, St. Louis, Missouri 63110, and.
authors.forename: Graydon B
authors.initials: GB
authors.lastname: Gereau
authors.affiliation: Washington University Pain Center, Department of Anesthesiology, St. Louis, Missouri 63110, and.
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Demaro
authors.affiliation: Neuroscience Department, Case Western Reserve University, Cleveland, Ohio 44106.
authors.forename: Gary E
authors.initials: GE
authors.lastname: Landreth
authors.affiliation: Washington University Pain Center, Department of Anesthesiology, St. Louis, Missouri 63110, and.
authors.forename: Judith P
authors.initials: JP
authors.lastname: Golden
authors.affiliation: Washington University Pain Center, Department of Anesthesiology, St. Louis, Missouri 63110, and gereaur@wustl.edu.
authors.forename: Robert W
authors.identifier: http://orcid.org/0000-0002-5428-4251
authors.initials: RW
authors.lastname: Gereau
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002470:Cell Survival / Q000502:physiology; D006930:Hyperalgesia / Q000378:metabolism*; D007150:Immunohistochemistry; D007249:Inflammation / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism*; D011984:Sensory Receptor Cells / Q000378:metabolism*
chemical_list: D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3
keywords: ERK; MAP kinase; MEK; nociception; pain; sensory neuron