KLHL1 Controls CaV3.2 Expression in DRG Neurons and Mechanical Sensitivity to Pain

MARTÍNEZ-HERNÁNDEZ, ELIZABETH; ZEGLIN, ALISSA; ALMAZAN, ERIK; PERISSINOTTI, PAULA; HE, YUNGUI; KOOB, MICHAEL; MARTIN, JODY L.; PIEDRAS-RENTERÍA, ERIKA S.

Frontiers in Molecular Neuroscience

Frontiers in Molecular Neuroscience

Año: 2020 vol. 12

Dorsal root ganglion (DRG) neurons process pain signaling through specializednociceptors located in their peripheral endings. It has long been established lowvoltage-activated (LVA) CaV3.2 calcium channels control neuronal excitability duringsensory perception in these neurons. Silencing CaV3.2 activity with antisense RNA orgenetic ablation results in anti-nociceptive, anti-hyperalgesic and anti-allodynic effects.CaV3.2 channels are regulated by many proteins (Weiss and Zamponi, 2017), includingKLHL1, a neuronal actin-binding protein that stabilizes channel activity by recycling itback to the plasma membrane through the recycling endosome. We explored whethermanipulation of KLHL1 levels and thereby function as a CaV3.2 modifier can modulateDRG excitability and mechanical pain transmission or sensitivity to pain. We firstassessed the mechanical sensitivity threshold and DRG properties in the KLHL1 KOmouse model. KO DRG neurons exhibited smaller T-type current density compared toWT without significant changes in voltage dependence, as expected in the absence ofits modulator. Western blot analysis confirmed CaV3.2 but not CaV3.1, CaV3.3, CaV2.1,or CaV2.2 protein levels were significantly decreased; and reduced neuron excitabilityand decreased pain sensitivity were also found in the KLHL1 KO model. Analogously,transient down-regulation of KLHL1 levels in WT mice with viral delivery of anti-KLHL1shRNA also resulted in decreased pain sensitivity. These two experimental approachesconfirm KLHL1 as a physiological modulator of excitability and pain sensitivity, providinga novel target to control peripheral pain.