A multi PDZ-domain protein Pdzd2 contributes to functional expression of sensory neuron-specific sodium channel Na(V)1.8.
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.
Shao
Dongmin
D
Division of Cell and Molecular Biology, Faculty of Natural Sciences, Imperial College London, London, UK.
Baker
Mark D
MD
Abrahamsen
Bjarke
B
Rugiero
Francois
F
Malik-Hall
Misbah
M
Poon
W-Y Louisa
WY
Cheah
Kathryn S E
KS
Yao
Kwok-Ming
KM
Wood
John N
JN
Okuse
Kenji
K
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
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