Regulation of somatosensory mechanotransduction by Annexin A6

Sensory neuron mechanically-activated slowly adapting currents have been linked to noxious mechanosensation. We identified a Conotoxin, Noxious Mechanosensation Blocker -1, that blocks such currents selectively. Using an active biotinylated form of the toxin we identified 67 binding proteins in sensory neurons and sensory neuron-derived cell lines using mass spectrometry. Annexin A6 was the most frequently identified binding protein. Annexin A6 knockout mice showed an enhanced sensitivity to mechanical stimuli. Rapidly adapting currents were enhanced and slowly adapting channels diminished. The percentage of neurons expressing slowly adapting currents fell and non-responsive neurons increased. Conversely, overexpression of annexin A6 in DRG neurons inhibited rapidly adapting currents without effects on slowly adapting currents. Co-expression of annexin A6 with Piezo 2 led to an inhibition of Piezo-mediated rapidly adapting currents. AAV-mediated gene delivery of annexin A6 to sensory neurons in a mouse model of osteoarthritis attenuated mechanical pain. These data demonstrate a role for annexin A6 in somatosensory mechanotransduction.