Specific Ion Channels Control Sensory Gain, Sensitivity, and Kinetics in a Tonic Thermonociceptor

Saro, Gabriella; Lia, Andrei-Stefan; Thapliyal, Saurabh; Marques, Filipe; Busch, Karl Emanuel; Glauser, Dominique A.

doi:10.1016/j.celrep.2019.12.029

Cited by 22 publications

(34 citation statements)

References 55 publications

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“…The time-lapse recordings were analyzed using LAS X software (Leica), adapting a previously described method 65 . Briefly, two regions of interest (ROI) were selected for each cell, and 50 cells per plate were chosen randomly.…”

Section: Methodsmentioning

confidence: 99%

PER2 mediates CREB-dependent light induction of the clock gene Per1

Brenna

Ripperger

Saro

et al. 2021

Sci Rep

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Light affects many physiological processes in mammals such as entrainment of the circadian clock, regulation of mood, and relaxation of blood vessels. At the molecular level, a stimulus such as light initiates a cascade of kinases that phosphorylate CREB at various sites, including serine 133 (S133). This modification leads CREB to recruit the co-factor CRCT1 and the histone acetyltransferase CBP to stimulate the transcription of genes containing a CRE element in their promoters, such as Period 1 (Per1). However, the details of this pathway are poorly understood. Here we provide evidence that PER2 acts as a co-factor of CREB to facilitate the formation of a transactivation complex on the CRE element of the Per1 gene regulatory region in response to light or forskolin. Using in vitro and in vivo approaches, we show that PER2 modulates the interaction between CREB and its co-regulator CRTC1 to support complex formation only after a light or forskolin stimulus. Furthermore, the absence of PER2 abolished the interaction between the histone acetyltransferase CBP and CREB. This process was accompanied by a reduction of histone H3 acetylation and decreased recruitment of RNA Pol II to the Per1 gene. Collectively, our data show that PER2 supports the stimulus-dependent induction of the Per1 gene via modulation of the CREB/CRTC1/CBP complex.

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Section: Methodsmentioning

confidence: 99%

PER2 mediates CREB-dependent light induction of the clock gene Per1

Brenna

Ripperger

Saro

et al. 2021

Sci Rep

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“…Ford et al (2018) reported that NALCN may contribute to neuronal excitability of spinal projection neurons. Additionally, the C. elegans NALCN gene, NCA-1, controls the thermal sensitivity of thermo-nociceptor and NCA-2 functions in thermal sensitivity, sensory gain maintenance, and signal kinetics during thermal stimuli termination (Saro et al, 2020). Eigenbrod et al (2019) showed that highveld mole-rat cells that expressed the NALCN gene produced a depolarized RMP to about −20 mV, which may induce a state unresponsive to normal stimuli.…”

Section: Discussionmentioning

confidence: 99%

Elevated Expression and Activity of Sodium Leak Channel Contributes to Neuronal Sensitization of Inflammatory Pain in Rats

Chen

Liu

et al. 2021

Front. Mol. Neurosci.

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Inflammatory pain encompasses many clinical symptoms, and there is no satisfactory therapeutic target. Neuronal hyperexcitability and/or sensitization of the primary nociceptive neurons in the dorsal root ganglion (DRG) and spinal dorsal horn are critical to the development and maintenance of inflammatory pain. The sodium leak channel (NALCN), a non-selective cation channel, mediates the background Na+ leak conductance and controls neuronal excitability. It is unknown whether abnormal activity of NALCN mediates the pathological process of inflammatory pain. Complete Freund’s adjuvant (CFA) was injected into the left footpad of rats to induce inflammatory pain. The thresholds of mechanical and thermal sensation and spontaneous pain behaviors were assessed. The expression of NALCN in DRG and spinal dorsal cord was measured. NALCN currents and the contribution of NALCN to neuronal excitability in the DRG and spinal dorsal cord were recorded using whole-cell patch-clamping recording. NALCN was abundantly expressed in neurons of the DRG and spinal dorsal cord. In acutely isolated DRG neurons and spinal cord slices from rats with CFA-induced inflammatory pain, NALCN currents and neuronal excitability were increased. Subsequently, intrathecal and sciatic nerve injection of NALCN-small interfering RNA (siRNA) decreased NALCN mRNA and reverted NALCN currents to normal levels, and then reduced CFA-induced neuronal excitability and alleviated pain symptoms. Furthermore, pain-related symptoms were significantly prevented by the NALCN-shRNA-mediated NALCN knockdown in DRG and spinal cord. Therefore, increased expression and activity of NALCN contributed to neuronal sensitization in CFA-induced inflammatory pain. NALCN may be a novel molecular target for the control of inflammatory pain.

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“…The time-lapse recordings were analyzed using LAS X software (Leica), adapting a previously described method 72 . Brie y, two regions of interest (ROI) were selected for each cell, and 50 cells per plate were chosen randomly.…”

Section: Fret Imaging Analysismentioning

confidence: 99%

PER2 Mediates CREB-Dependent Light Induction of Per1

Brenna

Ripperger

Saro

et al. 2021

Preprint

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Light affects many physiological processes in mammals such as entrainment of the circadian clock, regulation of mood, and relaxation of blood vessels. At the molecular level, a stimulus such as light initiates a cascade of kinases that phosphorylate CREB at various sites, including serine 133 (S133). This modification leads CREB to recruit the co-factor CRCT1 and the histone acetyltransferase CBP to stimulate the transcription of genes containing a CRE element in their promoters, such as Period 1 (Per1). However, the details of this pathway are poorly understood. Here we provide evidence that PER2 acts as a co-factor of CREB to facilitate the formation of a transactivation complex on the CRE element of the Per1 gene regulatory region in response to light. Using in vitro and in vivo approaches, we show that PER2 modulates the interaction between CREB and its co-regulator CRTC1 to support complex formation only after a light or forskolin stimulus. Furthermore, the absence of PER2 abolished the interaction between the histone acetyltransferase CBP and CREB. This process was accompanied by a reduction of histone H3 acetylation and decreased recruitment of RNA Pol II to the Per1 gene. Collectively, our data show that PER2 supports the stimulus-dependent induction of the Per1 gene via modulation of the CREB/CRTC1/CBP complex. Remarkably, our results indicate that the molecular mechanism that transduces the light signal to the clock is similar to the one in the filamentous fungus Neurospora crassa to induce frequency (Frq). This suggests an evolutionarily conserved mechanism of this process despite the divergent sequences of the individual components.

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Specific Ion Channels Control Sensory Gain, Sensitivity, and Kinetics in a Tonic Thermonociceptor

Cited by 22 publications

References 55 publications

PER2 mediates CREB-dependent light induction of the clock gene Per1

PER2 mediates CREB-dependent light induction of the clock gene Per1

Elevated Expression and Activity of Sodium Leak Channel Contributes to Neuronal Sensitization of Inflammatory Pain in Rats

PER2 Mediates CREB-Dependent Light Induction of Per1

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