Irregular Ca2+ Oscillations Regulate Transcription via Cumulative Spike Duration and Spike Amplitude

Song, Shanshan; Li, Jiansha; Zhu, Liping; Cai, Lei; Xu, Qian; Chen, Ling; Su, Yuan; Hu, Qinghua

doi:10.1074/jbc.m112.417154

Cited by 39 publications

(36 citation statements)

References 32 publications

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“…1A and Text S1, ESI†). Most calcium mathematical models exhibit continuous oscillations without decay in frequency or amplitude when subjected to step ligand stimulation, in contrast to our own experimental observations and literature data 29–31 . One model that does offer an explanation for frequency and amplitude decay 32 doesn’t explain the phase locking behavior we observe.…”

Section: Resultscontrasting

confidence: 99%

Band-pass processing in a GPCR signaling pathway selects for NFAT transcription factor activation

et al. 2015

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Many biological processes are rhythmic and proper timing is increasingly appreciated as being critical for development and maintenance of physiological functions. To understand how temporal modulation of an input signal influences downstream responses, we employ microfluidic pulsatile stimulation of a G-Protein coupled receptor, the muscarinic M3 receptor, in single cells with simultaneous real-time imaging of both intracellular calcium and NFAT nuclear localization. Interestingly, we find that reduced stimulation with pulses of ligand can give more efficient transcription factor activation, if stimuli are timed appropriately. Our experiments and computational analyses show that M3 receptor-induced calcium oscillations form a low pass filter while calcium-induced NFAT translocation forms a high pass filter. The combination acts as a band-pass filter optimized for intermediate frequencies of stimulation. We demonstrate that receptor desensitization and NFAT translocation rates determine critical features of the band-pass filter and that the band-pass may be shifted for different receptors or NFAT dynamics. As an example, we show that the two NFAT isoforms (NFAT4 and NFAT1) have shifted band-pass windows for the same receptor. While we focus specifically on the M3 muscarinic receptor and NFAT translocation, band-pass processing is expected to be a general theme that applies to multiple signaling pathways.

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Section: Resultscontrasting

confidence: 99%

Band-pass processing in a GPCR signaling pathway selects for NFAT transcription factor activation

et al. 2015

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“…The finding is also consistent with related studies on NFκB in immune cells (Song et al, 2012; Zhu et al, 2011) and the stimulus duration-dependent switching of cAMP-response element binding protein (CREB) in neurons (Bito et al, 1996, 1997), thus suggesting that decoding-by-integration is a general transcriptional principle applicable to many mammalian calcium-responsive activators. However, because these transcription factors differ from NFAT in terms of the presence of negative feedback loops mediated by IκB in NFκB signaling (Levine et al, 2013; Tay et al, 2010) and in terms CREB responsiveness to additional second messenger beyond calcium (Shaywitz and Greenberg, 1999), one should keep attuned to signaling network-specific differences in the decoding principles employed by different calcium-dependent transcription factors.…”

Section: Resultssupporting

confidence: 91%

Optogenetic Control of Calcium Oscillation Waveform Defines NFAT as an Integrator of Calcium Load

Hannanta‐anan

Chow

2016

Cell Systems

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SUMMARY It is known that the calcium-dependent transcription factor NFAT initiates transcription in response to pulsatile loads of calcium signal. However, the relative contributions of calcium oscillation frequency, amplitude, and duty cycle to transcriptional activity remain unclear. Here, we engineer HeLa cells to permit optogenetic control of intracellular calcium concentration using programmable LED arrays. This approach allows us to generate calcium oscillations of constant peak amplitude, in which frequency is varied while holding duty cycle constant, or vice versa. Using this setup and mathematical modeling, we show that NFAT transcriptional activity depends more on duty cycle, defined as the proportion of the integrated calcium concentration over the oscillation period, than on frequency alone. This demonstrates that NFAT acts primarily as a signal integrator of cumulative load rather than a frequency-selective decoder. This approach resolves a fundamental question in calcium encoding and demonstrates the value of optogenetics for isolating individual dynamical components of larger signaling behaviors.

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“…The most commonly expressed nAChR subtype is the ␣ 4 ␤ 2 -receptor (90%), which is characterized by its high affinity for acetylcholine (ACh) and nicotinic agonists (10,30 ] i oscillations are implicated in the regulation of neural plasticity (3, 26), which may be related to the increased efficiency and specificity of gene expression. Studies show both oscillation amplitude and frequency are critical for the regulation of gene expression and transcription (14,25).Although it has been reported that activation of nAChRs induces [Ca 2ϩ ] i oscillations, which is mediated by Ca 2ϩ influx and melatonin release from pinealocytes (17), the effect of nicotine on [Ca 2ϩ ] i oscillations in cortical neurons has not been reported. In this study, we investigated the nicotinic modulation of [Ca 2ϩ ] i oscillations in rat cortical neurons in primary culture and found that nicotinic enhancement of the oscillatory Ca 2ϩ signals is mediated through both ␣ 4 ␤ 2 -and ␣ 7 -nAChRs.…”

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Nicotinic modulation of Ca²⁺ oscillations in rat cortical neurons in vitro

Wang

Guo

et al. 2016

American Journal of Physiology-Cell Physiology

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roles of nicotine on Ca 2ϩ oscillations [intracellular Ca 2ϩ ([Ca 2ϩ ]i) oscillation] in rat primary cultured cortical neurons were studied. The spontaneous [Ca 2ϩ ]i oscillations (SCO) were recorded in a portion of the neurons (65%) cultured for 7-10 days in vitro. Application of nicotine enhanced [Ca 2ϩ ]i oscillation frequency and amplitude, which were reduced by the selective ␣4␤2-nicotinic acetylcholine receptors (nAChRs) antagonist dihydro-␤-erythroidine (DH␤E) hydrobromide, and the selective ␣7-nAChRs antagonist methyllycaconitine citrate (MLA, 20 nM). DH␤E reduced SCO frequency and prevented the nicotinic increase in the frequency. DH␤E somewhat enhanced SCO amplitude and prevented nicotinic increase in the amplitude. MLA (20 nM) itself reduced SCO frequency without affecting the amplitude but blocked nicotinic increase in [Ca 2ϩ ]i oscillation frequency and amplitude. Furthermore, coadministration of both ␣ 4␤2-and ␣7-nAChRs antagonists completely prevented nicotinic increment in [Ca 2ϩ ]i oscillation frequency and amplitude. Thus, our results indicate that both ␣ 4␤2-and ␣7-nAChRs mediated nicotine-induced [Ca 2ϩ ]i oscillations, and two nAChR subtypes differentially regulated SCO. intracellular calcium ion concentration oscillations; nicotine; ␣4␤2-nicotinic acetylcholine receptors; ␣7-nicotinic acetylcholine receptors; calcium NICOTINIC ACETYLCHOLINE RECEPTORS (nAChRs) mediate the excitability of neuronal circuits related to the memory, motivation, and mood (15, 16), are reduced in neurodegenerative and neuropsychiatric disorders such as schizophrenia and Alzheimer's disease (6,22,24), and have been proposed as potential therapeutic targets for these diseases (13,28).At least four different nAChR subtypes, non-␣ 7 (␣ 2 , ␣ 3 ␤ 4 , ␣ 4 ␤ 2 )-and ␣ 7 -nAChRs, are expressed in the cortex. The most commonly expressed nAChR subtype is the ␣ 4 ␤ 2 -receptor (90%), which is characterized by its high affinity for acetylcholine (ACh) and nicotinic agonists (10,30 ] i oscillations are implicated in the regulation of neural plasticity (3, 26), which may be related to the increased efficiency and specificity of gene expression. Studies show both oscillation amplitude and frequency are critical for the regulation of gene expression and transcription (14,25).Although it has been reported that activation of nAChRs induces [Ca 2ϩ ] i oscillations, which is mediated by Ca 2ϩ influx and melatonin release from pinealocytes (17), the effect of nicotine on [Ca 2ϩ ] i oscillations in cortical neurons has not been reported. In this study, we investigated the nicotinic modulation of [Ca 2ϩ ] i oscillations in rat cortical neurons in primary culture and found that nicotinic enhancement of the oscillatory Ca 2ϩ signals is mediated through both ␣ 4 ␤ 2 -and ␣ 7 -nAChRs. MATERIALS AND METHODS Cortical neuronal cultures.Primary cultures of cortical neurons were prepared from 17-to 18-day-old Sprague-Dawley rat embryos as described previously (14a). All cell culture reagents were purchased from Invitrog...

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Irregular Ca2+ Oscillations Regulate Transcription via Cumulative Spike Duration and Spike Amplitude

Cited by 39 publications

References 32 publications

Band-pass processing in a GPCR signaling pathway selects for NFAT transcription factor activation

Band-pass processing in a GPCR signaling pathway selects for NFAT transcription factor activation

Optogenetic Control of Calcium Oscillation Waveform Defines NFAT as an Integrator of Calcium Load

Nicotinic modulation of Ca²⁺ oscillations in rat cortical neurons in vitro

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Irregular Ca2+ Oscillations Regulate Transcription via Cumulative Spike Duration and Spike Amplitude

Cited by 39 publications

References 32 publications

Band-pass processing in a GPCR signaling pathway selects for NFAT transcription factor activation

Band-pass processing in a GPCR signaling pathway selects for NFAT transcription factor activation

Optogenetic Control of Calcium Oscillation Waveform Defines NFAT as an Integrator of Calcium Load

Nicotinic modulation of Ca2+ oscillations in rat cortical neurons in vitro

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Nicotinic modulation of Ca²⁺ oscillations in rat cortical neurons in vitro