IndraLab
Statements
sparser
"Lamina II (substantia gelatinosa (SG)) neurons in the superficial spinal dorsal horn (SDH) are the second-order sensory neurons, which primarily receive and modulate nociceptive inputs from the myelinated Aδ and unmyelinated C fibers. xref Therefore, the increasing excitatory process of SG neuron is one of the most important mechanisms for the central sensitization of pathological pain. xref Recently, a Cav3.2-dependent link of SG neuronal excitability and cutaneous transient receptor potential vanilloid-1 (TRPV1) expressing nociceptors has been demonstrated. xref Conditioning stimulation of optogenetically targeted cutaneous TRPV1 expressing nociceptors could evoke an increase in C-fiber activity, which may, in turn, lead to an enhanced presynaptic excitatory neurotransmission in SG neurons. xref Moreover, either Ni 2+ (a blocker of Cav3 channels) or Tat-3.2-III-IV peptide (a blocker of USP5-Cav3.2 association) could decrease the frequency of excitatory postsynaptic currents in SG neurons, strongly suggesting a role of Cav3.2 in the sensitization of the pain pathway mentioned above. xref , xref Therefore, the potentiation of presynaptic Cav3.2 channels may contribute to the hyperexcitability of SG neurons, accompanying with the promotion of chronic pain."
sparser
"No significant effects on current amplitude or biophysical properties of the channel were observed (7±2% inhibition (n=3) and 3±1% inhibition (n=3) of channel activity for suramin and gossypetin, respectively, which is indistinguishable from rundown), consistent with an action on the USP5-Cav3.2 channel interaction rather than direct effects on Cav3.2 channel function."
reach
"The acute sensitization initiated by optical stimulation (10 Hz) of TRPV1-ChR2 neurons, is sufficient to increase USP5 expression, which results in increased Cav3.2 T-type activity and increased mechanical hypersensitivity that is dependent on the interaction of USP5 and Cav3.2 [104]."
sparser
"The acute sensitization initiated by optical stimulation (10 Hz) of TRPV1-ChR2 neurons, is sufficient to increase USP5 expression, which results in increased Cav3.2 T-type activity and increased mechanical hypersensitivity that is dependent on the interaction of USP5 and Cav3.2 [ xref ]."
sparser
"We have previously reported that pain hypersensitivity in diabetic ob/ob mice can be reversed by blocking the interactions between USP5 and Cav3.2 by small organic molecule mimetics. xref To determine whether the TAT-cUBP1-USP5 peptide was similarly effective, we assessed thermal withdrawal threshold in ob/ob mice before and after delivery of the TAT-cUBP1-USP5 peptide."
sparser
"Consistent with our observations, this region has been previously described as a potential site for substrate targeting and specificity. xref In contrast, this region does not appear to be important for substrate modification by the catalytic site because deletion of the cUBP (163–291) domain did not affect the hydrolysis rate of ubiquitin-AMC. xref Together with our previous identification of a short (∼20 amino acid) stretch of residues in the domain III-IV linker of the Cav3.2 channel, xref we now have two complementary tools that allow us to disrupt USP5-Cav3.2 interactions both in vitro and in vivo."
sparser
"Since this process is relevant to both inflammatory and neuropathic pain states, xref , xref we initially proposed that neural activity may be a common trigger. xref This idea was supported by observations that activity stemming from optogenetically targeted cutaneous nociceptors alone is sufficient to upregulate USP5 expression, and therefore to increase interactions between USP5 and Cav3.2. xref However, this activity-dependent phenomenon is not self-sustaining, instead promoting only a transient pain state that cannot account for the upregulation observed after injury."
reach
"Using an intrathecal injection of a permeant peptide which impairs the interaction between USP5 and CaV3.2, several studies showed that it was possible to relieve rapidly (in a few minutes) pain sensation related to mechanical or thermal hypersensitivity.As a conclusion, many approaches using permeant peptides but also nonpeptidic synthetic molecules [42,43] have managed to alter the interaction between voltage-dependent calcium channel partners in order to successfully reverse various symptoms associated with different pathologies."
sparser
"While the above findings support the hypothesis that IL-1β drives upregulation of T-type channels via USP5 to induce pain, these effects were studied under acute conditions (<1 h) that yield transient pain (∼15 min) and may be secondary to interactions between IL-1β and glial cells, which are known to express IL-1RI. xref , xref To study neuroinflammatory interaction more directly, while reflecting sustained release after physical injury, we used DRG neuron cultures to evaluate the level of USP5 bound to Cav3.2 in response to overnight (∼24 h) exposure to IL-1β."
sparser
"Under these conditions and relative to vehicle control (0.1% BSA in PBS), IL-1β produced a clear increase in the level of interaction between USP5 and Cav3.2 channels in co-IP experiments ( xref and ( xref )), which is mediated by IL-1RI, as this effect was almost completely attenuated in the presence of IL-1Ra (100 ng/ml)."
reach
"It is interesting that in a preliminary in vitro screen of potential mediators, which included brain-derived neurotrophic factor, nerve growth factor, and tumor necrosis factor-alpha, none were as effective as IL-1β at inducing interactions between USP5 and Cav3.2 (data not shown)."
sparser
"When the SUMOylation of USP5 is decreased, there is an increase in the interactions between USP5 and Cav3.2 calcium channels. xref The KRas indirectly regulates USP5 activity by upregulating cellular ROS levels, leading to the formation of USP5 homodimers, enhanced USP5 enzymatic activity, and the accumulation of USP5 protein. xref Long non-coding RNAs (LncRNAs) interact with specific proteins to regulate downstream effectors."
sparser
"It is interesting that in a preliminary in vitro screen of potential mediators, which included brain-derived neurotrophic factor, nerve growth factor, and tumor necrosis factor-alpha, none were as effective as IL-1β at inducing interactions between USP5 and Cav3.2 (data not shown)."