title: A multi PDZ-domain protein Pdzd2 contributes to functional expression of sensory neuron-specific sodium channel Na(V)1.8.
abstract: The voltage-gated sodium channel Na(V)1.8 is expressed exclusively in nociceptive sensory neurons and plays an important role in pain pathways. Na(V)1.8 cannot be functionally expressed in non-neuronal cells even in the presence of beta-subunits. We have previously identified Pdzd2, a multi PDZ-domain protein, as a potential interactor for Na(V)1.8. Here we report that Pdzd2 binds directly to the intracellular loops of Na(V)1.8 and Na(V)1.7. The endogenous Na(V)1.8 current in sensory neurons is inhibited by antisense- and siRNA-mediated downregulation of Pdzd2. However, no marked change in pain behaviours is observed in Pdzd2-decificent mice. This may be due to compensatory upregulation of p11, another regulatory factor for Na(V)1.8, in dorsal root ganglia of Pdzd2-deficient mice. These findings reveal that Pdzd2 and p11 play collaborative roles in regulation of Na(V)1.8 expression in sensory neurons.
authors.affiliation: Division of Cell and Molecular Biology, Faculty of Natural Sciences, Imperial College London, London, UK.
authors.forename: Dongmin
authors.initials: D
authors.lastname: Shao
authors.forename: Mark D
authors.initials: MD
authors.lastname: Baker
authors.forename: Bjarke
authors.initials: B
authors.lastname: Abrahamsen
authors.forename: Francois
authors.initials: F
authors.lastname: Rugiero
authors.forename: Misbah
authors.initials: M
authors.lastname: Malik-Hall
authors.forename: W-Y Louisa
authors.initials: WY
authors.lastname: Poon
authors.forename: Kathryn S E
authors.initials: KS
authors.lastname: Cheah
authors.forename: Kwok-Ming
authors.initials: KM
authors.lastname: Yao
authors.forename: John N
authors.initials: JN
authors.lastname: Wood
authors.forename: Kenji
authors.initials: K
authors.lastname: Okuse
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000595:Amino Acid Sequence; D000818:Animals; D015815:Cell Adhesion Molecules; D002478:Cells, Cultured; D005727:Ganglia, Spinal / Q000166:cytology; D051379:Mice; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D062556:NAV1.7 Voltage-Gated Sodium Channel; D062559:NAV1.8 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D054731:PDZ Domains; D010146:Pain / Q000378:metabolism; D010147:Pain Measurement; D011485:Protein Binding; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D011984:Sensory Receptor Cells / Q000166:cytology / Q000378:metabolism*; D016415:Sequence Alignment; D015222:Sodium Channels / Q000235:genetics / Q000378:metabolism*; D020798:Two-Hybrid System Techniques
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D015815:Cell Adhesion Molecules; D062556:NAV1.7 Voltage-Gated Sodium Channel; D062559:NAV1.8 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins; C414604:PDZD2 protein, rat; C545704:Pdzd2 protein, mouse; D034741:RNA, Small Interfering; D011993:Recombinant Fusion Proteins; C568318:Scn10a protein, mouse; C568319:Scn10a protein, rat; C503480:Scn9a protein, rat; D015222:Sodium Channels