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.