Transcriptional repressor DREAM regulates trigeminal noxious perception

Benedet, Tomaso; González, Paz; Oliveros, Juan Carlos; Dopazo, Jose M.; Ghimire, Kedar; Palczewska, Małgorzata; Mellström, Britt; Naranjo, José R.

doi:10.1111/jnc.13584

Cited by 15 publications

(13 citation statements)

References 51 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Attenuation of central sensitization due to reduced Bdnf gene expression contributed to the hypoalgesic behavior of the transgenic mice. Recently, it was reported that another line of daDREAM mice (with daDREAM expression in trigeminal ganglia) showed a significant increase in the rubbing response in the first and second phases of the formalin test, which might be correlated with decreased expression of Pdyn (Benedet et al, 2017). Conversely, the nocifensive response to 4.5% formalin injection in the snoot in Kcnip3 -/- mice was milder than that in normal mice.…”

Section: Discussionmentioning

confidence: 99%

“…Increased intracellular Ca 2+ concentration can prevent binding of DREAM to the DRE site and derepress DRE-dependent gene expression. Functional expression of DREAM in cortex, hippocampus, cerebellum, spinal cord, dorsal root ganglion (DRG), pineal gland, thyroid and blood cells was validated, and numerous target genes of DREAM were identified, including Fos, Pdyn (prodynorphin), Slc8a3 (solute carrier family 8 member A3), Npas4 (neuronal PAS domain protein 4) and Bdnf (brain-derived neurotrophic factor) (Table 1) (Carrion et al, 1998, 1999; Sanz et al, 2001, 2002; Link et al, 2004; Rivas et al, 2004; D’Andrea et al, 2005; Gomez-Villafuertes et al, 2005; Savignac et al, 2005; Venn et al, 2008; Dierssen et al, 2012; Mellstrom et al, 2014; Benedet et al, 2017). Actually, DREAM is identical to KChIP3 (Kv4 channel interacting protein 3), a member of the KChIPs family, which is composed of KChIP1, 2, 3 and 4.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Global Gene Knockout of Kcnip3 Enhances Pain Sensitivity and Exacerbates Negative Emotions in Rats

Guo

Zhi

Liu

et al. 2019

Front. Mol. Neurosci.

View full text Add to dashboard Cite

The Ca2+-binding protein Kv channel interacting protein 3 (KChIP3) or downstream regulatory element antagonist modulator (DREAM), a member of the neuronal calcium sensor (NCS) family, shows remarkable multifunctional properties. It acts as a transcriptional repressor in the nucleus and a modulator of ion channels or receptors, such as Kv4, NMDA receptors and TRPV1 channels on the cytomembrane. Previous studies of Kcnip3-/- mice have indicated that KChIP3 facilitates pain hypersensitivity by repressing Pdyn expression in the spinal cord. Conversely, studies from transgenic daDREAM (dominant active DREAM) mice indicated that KChIP3 contributes to analgesia by repressing Bdnf expression and attenuating the development of central sensitization. To further determine the role of KChIP3 in pain transmission and its possible involvement in emotional processing, we assessed the pain sensitivity and negative emotional behaviors of Kcnip3-/- rats. The knockout rats showed higher pain sensitivity compared to the wild-type rats both in the acute nociceptive pain model and in the late phase (i.e., 2, 4 and 6 days post complete Freund’s adjuvant injection) of the chronic inflammatory pain model. Importantly, Kcnip3-/- rats displayed stronger aversion to the pain-associated compartment, higher anxiety level and aggravated depression-like behavior. Furthermore, RNA-Seq transcriptional profiling of the forebrain cortex were compared between wild-type and Kcnip3-/- rats. Among the 68 upregulated genes, 19 genes (including Nr4a2, Ret, Cplx3, Rgs9, and Itgad) are associated with neural development or synaptic transmission, particularly dopamine neurotransmission. Among the 79 downregulated genes, 16 genes (including Col3a1, Itm2a, Pcdhb3, Pcdhb22, Pcdhb20, Ddc, and Sncaip) are associated with neural development or dopaminergic transmission. Transcriptional upregulation of Nr4a2, Ret, Cplx3 and Rgs9, and downregulation of Col3a1, Itm2a, Pcdhb3 and Ddc, were validated by qPCR analysis. In summary, our studies showed that Kcnip3-/- rats displayed higher pain sensitivity and stronger negative emotions, suggesting an involvement of KChIP3 in negative emotions and possible role in central nociceptive processing.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Global Gene Knockout of Kcnip3 Enhances Pain Sensitivity and Exacerbates Negative Emotions in Rats

Guo

Zhi

Liu

et al. 2019

Front. Mol. Neurosci.

View full text Add to dashboard Cite

show abstract

“…KCNIP3 mutants with two amino acids substitution in the EF-hands two, three, and four are unable to respond to Ca 2+ and function as a constitutively dominant active (daDREAM) transcriptional repressor (Savignac et al, 2005). In transgenic mice with neuronal expression of this daDREAM, the CAMK2A mRNA level is reduced by 1.7-fold compared to wild type (Benedet et al, 2017). Mouse promoter for KCNN4 is conserved (79%), but in a lesser extend concerning DRE sequences.…”

Section: Regulation Of Gbm Prognosis Genes By Kcnip Proteinsmentioning

confidence: 94%

Ca2+-Dependent Transcriptional Repressors KCNIP and Regulation of Prognosis Genes in Glioblastoma

Néant

Haiech

Kilhoffer

et al. 2018

Front. Mol. Neurosci.

View full text Add to dashboard Cite

Glioblastomas (GBMs) are the most aggressive and lethal primary astrocytic tumors in adults, with very poor prognosis. Recurrence in GBM is attributed to glioblastoma stem-like cells (GSLCs). The behavior of the tumor, including proliferation, progression, invasion, and significant resistance to therapies, is a consequence of the self-renewing properties of the GSLCs, and their high resistance to chemotherapies have been attributed to their capacity to enter quiescence. Thus, targeting GSLCs may constitute one of the possible therapeutic challenges to significantly improve anti-cancer treatment regimens for GBM. Ca2+ signaling is an important regulator of tumorigenesis in GBM, and the transition from proliferation to quiescence involves the modification of the kinetics of Ca2+ influx through store-operated channels due to an increased capacity of the mitochondria of quiescent GSLC to capture Ca2+. Therefore, the identification of new therapeutic targets requires the analysis of the calcium-regulated elements at transcriptional levels. In this review, we focus onto the direct regulation of gene expression by KCNIP proteins (KCNIP1–4). These proteins constitute the class E of Ca2+ sensor family with four EF-hand Ca2+-binding motifs and control gene transcription directly by binding, via a Ca2+-dependent mechanism, to specific DNA sites on target genes, called downstream regulatory element (DRE). The presence of putative DRE sites on genes associated with unfavorable outcome for GBM patients suggests that KCNIP proteins may contribute to the alteration of the expression of these prognosis genes. Indeed, in GBM, KCNIP2 expression appears to be significantly linked to the overall survival of patients. In this review, we summarize the current knowledge regarding the quiescent GSLCs with respect to Ca2+ signaling and discuss how Ca2+ via KCNIP proteins may affect prognosis genes expression in GBM. This original mechanism may constitute the basis of the development of new therapeutic strategies.

show abstract

“…Initially identified as calsenilin, a presenilin binding protein [5], was rapidly recognized also as a transcriptional repressor through the association with DRE (Downstream Regulatory Element) sites [6], and a potassium channel interacting protein (KChIP3) that regulates the intracellular traffic and biophysical properties of K v 4 channels [7]. Besides modifying the expression of several genes involved in pain perception, like c-fos [6], brain derived neurotrophic factor (BDNF) [8,9], prodynorphin [6,10], cathepsin L [11] or interleukins 2 and 4 [12], DREAM also interacts with a variety of ion channels and receptors involved in pain detection and transmission in DRG neurons. This is the case of NMDA glutamate receptors [13], TRPV1 channels [14], and a variety of voltage-activated channels, including K v 4.3 channels responsible for the transient, A-type, potassium current (I A ) [15], and the low, T-type [16], and high voltage-activated (HVA), L-type [17] Ca v channels.…”

Section: Introductionmentioning

confidence: 99%

IQM-PC332, a Novel DREAM Ligand with Antinociceptive Effect on Peripheral Nerve Injury-Induced Pain

Socuéllamos

Olivos-Oré

Barahona

et al. 2022

IJMS

View full text Add to dashboard Cite

Neuropathic pain is a form of chronic pain arising from damage of the neural cells that sense, transmit or process sensory information. Given its growing prevalence and common refractoriness to conventional analgesics, the development of new drugs with pain relief effects constitutes a prominent clinical need. In this respect, drugs that reduce activity of sensory neurons by modulating ion channels hold the promise to become effective analgesics. Here, we evaluated the mechanical antinociceptive effect of IQM-PC332, a novel ligand of the multifunctional protein downstream regulatory element antagonist modulator (DREAM) in rats subjected to chronic constriction injury of the sciatic nerve as a model of neuropathic pain. IQM-PC332 administered by intraplantar (0.01–10 µg) or intraperitoneal (0.02–1 µg/kg) injection reduced mechanical sensitivity by ≈100% of the maximum possible effect, with ED50 of 0.27 ± 0.05 µg and 0.09 ± 0.01 µg/kg, respectively. Perforated-patch whole-cell recordings in isolated dorsal root ganglion (DRG) neurons showed that IQM-PC332 (1 and 10 µM) reduced ionic currents through voltage-gated K+ channels responsible for A-type potassium currents, low, T-type, and high voltage-activated Ca2+ channels, and transient receptor potential vanilloid-1 (TRPV1) channels. Furthermore, IQM-PC332 (1 µM) reduced electrically evoked action potentials in DRG neurons from neuropathic animals. It is suggested that by modulating multiple DREAM–ion channel signaling complexes, IQM-PC332 may serve a lead compound of novel multimodal analgesics.

show abstract

Transcriptional repressor DREAM regulates trigeminal noxious perception

Cited by 15 publications

References 51 publications

Global Gene Knockout of Kcnip3 Enhances Pain Sensitivity and Exacerbates Negative Emotions in Rats

Global Gene Knockout of Kcnip3 Enhances Pain Sensitivity and Exacerbates Negative Emotions in Rats

Ca2+-Dependent Transcriptional Repressors KCNIP and Regulation of Prognosis Genes in Glioblastoma

IQM-PC332, a Novel DREAM Ligand with Antinociceptive Effect on Peripheral Nerve Injury-Induced Pain

Contact Info

Product

Resources

About