Cumulated Ca2+ spike duration underlies Ca2+ oscillation frequency-regulated NFκB transcriptional activity

Journal of Cell Science, Aug 2011

Liping Zhu, Shanshan Song, Yubo Pi, Yang Yu, Weibin She, Hong Ye, Yuan Su, Qinghua Hu

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Cumulated Ca2+ spike duration underlies Ca2+ oscillation frequency-regulated NFκB transcriptional activity

Liping Zhu 1 2 Shanshan Song 1 2 Yubo Pi 1 2 Yang Yu 1 2 Weibin She 1 2 Hong Ye 1 2 Yuan Su 0 1 Qinghua Hu () 1 2 3 0 Department of Respiratory Medicine, Union Hospital, Tongji Medical College, Huazhong Science and Technology University , Wuhan 430030, People's Republic of China 1 Key Laboratory of Pulmonary Diseases of Ministry of Health of China, Tongji Medical College, Huazhong Science and Technology University , Wuhan 430030, People's Republic of China 2 Department of Pathophysiology, Tongji Medical College, Huazhong Science and Technology University , Wuhan 430030, People's Republic of China 3 The MOE Key Laboratory of Environment and Health, School of Public Health, Tongji Medical College, Huazhong Science and Technology University , Wuhan 430030, People's Republic of China - Summary ce [Ca2+]i oscillations drive downstream events, like transcription, in a frequency-dependent manner. Why [Ca2+]i oscillation frequency n regulates transcription has not been clearly revealed. A variation in [Ca2+]i oscillation frequency apparently leads to a variation in the ic time duration of cumulated [Ca2+]i elevations or cumulated [Ca2+]i spike duration. By manipulating [Ca2+]i spike duration, we e S generated a series of [Ca2+]i oscillations with the same frequency but different cumulated [Ca2+]i spike durations, as well as [Ca2+]i lle oscillations with the different frequencies but the same cumulated [Ca2+]i spike duration. Molecular assays demonstrated that, when C generated in artificial models alone, under physiologically simulated conditions or repetitive pulses of agonist exposure, [Ca2+]i fo oscillation regulates NFkB transcriptional activity, phosphorylation of IkBa and Ca2+-dependent gene expression all in a way actually la dependent on cumulated [Ca2+]i spike duration whether or not frequency varies. This study underlines that [Ca2+]i oscillation frequency rn regulates NFkB transcriptional activity through cumulated [Ca2+]i spike-duration-mediated IkBa phosphorylation. u o J Introduction [Ca2+]i oscillations, a series of repetitive [Ca2+]i spikes, were first demonstrated in hepatocytes (Woods et al., 1986) and have been observed in almost all non-excitable cells ever studied. Investigation over the past two decades has established (Berridge et al., 2003; Jacob et al., 1988) that [Ca2+]i oscillation regulates cellular downstream events, including transcription, through its frequency (Colella et al., 2008; De Koninck and Schulman, 1998; Dolmetsch et al., 1998; Hajnoczky et al., 1995; Hu et al., 1999; Li et al., 1998; Tomida et al., 2003; Zhu et al., 2008). Frequency-dependent regulation of downstream events is generally important because it provides advantages over amplitude-dependent regulation (Berridge et al., 2003; Jacob et al., 1988), it regulates transcription more efficiently and specifically than sustained [Ca2+]i elevations (Dolmetsch et al., 1998; Tomida et al., 2003) and also efficiently cooperates with intracellular reactive oxygen species (ROS) in regulating nuclear factor kB (NFkB) transcriptional activity and subsequent gene expression (Zhu et al., 2008). Dynamic differences between dephosphorylation of cytoplasmic nuclear factor of activated T-cells (NFAT) and rephosphorylation of nucleoplasmic NFAT has been suggested as an explanation for how [Ca2+]i oscillation regulates NFAT activation (Tomida et al., 2003). To the best of our knowledge, however, there has never been an experimental attempt to address why [Ca2+]i oscillation frequency by itself regulates downstream events, such as transcription, leaving a fundamental issue unsolved. Apparently, when [Ca2+]i oscillates for a period of time, a long cumulated time duration of [Ca2+]i elevation accompanies a high frequency of oscillation and vice versa. Here, we hypothesized that [Ca2+]i oscillation frequency regulates transcription through a mechanism associated with the cumulated time duration of [Ca2+]i elevations. The cumulated time duration of [Ca2+]i elevations is controlled by frequency, but another determinant is [Ca2+]i spike duration (SD) or [Ca2+]i spike width, which is profoundly modulated by a variety of extracellular and intracellular conditions or physiological and pathophysiological circumstances, such as agonist species and their concentration (Cobbold et al., 1991; Moccia et al., 2003; Morgan and Jacob, 1998; Shuttleworth and Thompson, 1996), extracellular Ca2+ concentration (Igarashi et al., 1997; Zhao et al., 1990), extracellular pH (Jackson and Thayer, 2006; Zhao et al., 1990), the endoplasmic reticulum Ca2+-ATPase (Morgan and Jacob, 1998; Petersen et al., 1993), protein kinase C (PKC) (Young et al., 2002), mitochondria (Jackson and Thayer, 2006) and even temperature (Lee et al., 2005; Schipke et al., 2008; Szekely et al., 2009). When [Ca2+]i SD varies, the same frequency of [Ca2+]i oscillations have a different cumulated time duration of [Ca2+]i elevation or cumulated [Ca2+]i spike duration (CSD). Related to our hypo (...truncated)


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Liping Zhu, Shanshan Song, Yubo Pi, Yang Yu, Weibin She, Hong Ye, Yuan Su, Qinghua Hu. Cumulated Ca2+ spike duration underlies Ca2+ oscillation frequency-regulated NFκB transcriptional activity, Journal of Cell Science, 2011, pp. 2591-2601, 124/15, DOI: 10.1242/jcs.082727