Chronic pain can be a severely debilitating condition that reflects a long term sensitization of signal transduction in the afferent pain pathway.  Among the key players in the afferent pain pathway are T-type calcium channels, whose activities are aberrantly enhanced under conditions of inflammatory and neuropathic pain.  In this context, we discovered that the plasma membrane expression of the Cav3.2 T-type channel subtype is under dynamic control by ubiquitinating and deubiquitinating enzymes. Importantly, we were able to show that peripheral inflammation or nerve injury promotes the association of the deubiquitinase USP5 with the channel, leading to increased T-type channel activity in afferent fibers, and consequently pain hypersensitivity.  Conversely, disruption of this process by decoy peptides alleviated pain hypersensitivity.  The USP5 dependent process is activity dependent as evident from transcutaneous optogenetic stimulation of afferent fibers, and is regulated by interleukin 33.  We developed a high throughput screen to identify novel small organic USP5 disruptors, leading to the discovery of a new class of analgesic molecules that are effective in mouse models of inflammatory and neuropathic pain.  Finally, we describe preliminary data from a mouse model that harbors a pathogenic mutation in USP5 that has been linked to congenital insensitivity to pain in a pediatric patient.

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