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GCaMP
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<h2 id="structure">Structure</h2> <p>GCaMP consists of three key domains: an M13 domain at the <a href="/facts/N-terminus/yKYpuaBJ">N-terminus</a>, a calmodulin (CaM) domain at the <a href="/facts/C-terminus/ws4scHgT">C-terminus</a>, and a GFP domain in the center. The GFP domain is <a href="/facts/Circular_permutation_in_proteins/24bECY8x">circularly permuted</a> such that the native N- and C-termini are fused together by a six-<a href="/facts/Amino_acid/WDxYwBny">amino-acid</a> linking sequence, and the GFP sequence is split in the middle, creating new N- and C-termini that connect to the M13 and CaM domains.<a class="footnote-ref" id="fnref:7" href="#fn:7"><sup>7</sup></a> </p><p>In the absence of Ca2+, the GFP <a href="/facts/Chromophore/9RykVkek">chromophore</a> is exposed to water and exists in a protonated state with minimal fluorescence intensity. Upon Ca2+ binding, the CaM domain undergoes a conformational change and tightly binds to the M13 domain <a href="/facts/Alpha_helix/7CESPIYJ">alpha helix</a>, preventing water molecules from accessing the chromophore. As a result, the chromophore rapidly deprotonates and converts into an anionic form that fluoresces brightly, similar to native GFP.<a class="footnote-ref" id="fnref:8" href="#fn:8"><sup>8</sup></a> </p> <h2 id="history-and-development">History and development</h2> <p>In 2001, Nakai et al. reported the development of GCaMP1 as a Ca2+ probe with improved <a href="/facts/Signal-to-noise_ratio/qohClhyG">signal-to-noise ratio</a> compared to previously developed fluorescent Ca2+ probes.<a class="footnote-ref" id="fnref:9" href="#fn:9"><sup>9</sup></a> The first transgenic <a href="/facts/Mouse/6m1X7m0g">mouse</a> expressing GCaMP1 was reported in 2004.<a class="footnote-ref" id="fnref:10" href="#fn:10"><sup>10</sup></a> However, at 37 ˚C (physiological temperature in mammals), GCaMP1 did not fold stably or fluoresce, limiting its potential use as a calcium indicator <i>in vivo.</i><a class="footnote-ref" id="fnref:11" href="#fn:11"><sup>11</sup></a><a class="footnote-ref" id="fnref:12" href="#fn:12"><sup>12</sup></a> </p><p>In 2006, Tallini et al. subsequently reported the improvement of GCaMP1 to GCaMP2, which exhibited brighter fluorescence than GCaMP1 and greater stability at <a href="/facts/Mammal/phSwTzBo">mammalian</a> body temperatures. Tallini et al. expressed GCaMP2 in <a href="/facts/Cardiac_muscle_cell/fE40oTQz">cardiomyocytes</a> in mouse embryos to perform the first <i>in vivo</i> GCaMP imaging of Ca2+ in mammals.<a class="footnote-ref" id="fnref:13" href="#fn:13"><sup>13</sup></a> </p><p>Further modifications of GCaMP, including GCaMP3, GCaMP5, GCaMP6, and jGCaMP7, have been developed to progressively improve the signal, <a href="/facts/Sensitivity_and_specificity/pzc9qfdz">sensitivity</a>, and <a href="/facts/Dynamic_range/zxcuI4Fn">dynamic range</a> of Ca2+ detection,<a class="footnote-ref" id="fnref:14" href="#fn:14"><sup>14</sup></a><a class="footnote-ref" id="fnref:15" href="#fn:15"><sup>15</sup></a><a class="footnote-ref" id="fnref:16" href="#fn:16"><sup>16</sup></a><a class="footnote-ref" id="fnref:17" href="#fn:17"><sup>17</sup></a> with recent versions exhibiting fluorescence similar to native GFP.<a class="footnote-ref" id="fnref:18" href="#fn:18"><sup>18</sup></a> </p> <h3>Variants in use</h3> <p>Both slow variants (GCaMP6s, jGCaMP7s) and fast variants (GCaMP6f, jGCaMP7f) are used in biological and <a href="/facts/Neuroscience/o5RV8Cas">neuroscience</a> research. The slow variants are brighter and more sensitive to small changes in Ca2+ levels, such as single <a href="/facts/Action_potential/Sz8yCRqx">action potentials</a>; on the other hand, the fast variants are less sensitive but respond more quickly, making them useful for tracking changes in Ca2+ levels over precise timescales.<a class="footnote-ref" id="fnref:19" href="#fn:19"><sup>19</sup></a><a class="footnote-ref" id="fnref:20" href="#fn:20"><sup>20</sup></a> GCaMP6 also has a medium variant, GCaMP6m, whose kinetics are intermediate between GCaMP6s and GCaMP6f.<a class="footnote-ref" id="fnref:21" href="#fn:21"><sup>21</sup></a> Other variants of jGCaMP7 are also employed: jGCaMP7b exhibits bright baseline fluorescence and is used for imaging <a href="/facts/Dendrite/bwv8MABY">dendrites</a> and <a href="/facts/Axon/5DCd4wLo">axons</a>, while jGCaMP7c exhibits greater contrast between maximal and baseline fluorescence and is advantageous for imaging large populations of neurons.<a class="footnote-ref" id="fnref:22" href="#fn:22"><sup>22</sup></a> </p><p>In 2018, Yang et al. reported the development of GCaMP-X, generated by the addition of a calmodulin-binding motif. Since the GCaMP calmodulin domain, when unbound, disrupts <a href="/facts/L-type_calcium_channel/4vbqP8B7">L-type calcium channel</a> gating, the added calmodulin-binding motif prevents GCaMP-X from interfering with calcium-dependent signaling mechanisms.<a class="footnote-ref" id="fnref:23" href="#fn:23"><sup>23</sup></a> </p><p>In 2020, Zhang et al. reported the development of jGCaMP8, including sensitive, medium, and fast variants, which exhibit faster kinetics and greater sensitivity than the corresponding jGCaMP7 variants.<a class="footnote-ref" id="fnref:24" href="#fn:24"><sup>24</sup></a> </p><p>Red fluorescent indicators have also been developed: jRCaMP1a and jRCaMP1b use a circular permutation of the <a href="/facts/Red_fluorescent_protein/XXej1etn">red fluorescent protein</a> mRuby instead of GFP, while jRGECO1a is based on the red fluorescent protein mApple.<a class="footnote-ref" id="fnref:25" href="#fn:25"><sup>25</sup></a><a class="footnote-ref" id="fnref:26" href="#fn:26"><sup>26</sup></a> Since the blue light used to excite GCaMP is scattered by tissue and the emitted green light is absorbed by blood, red fluorescent indicators provide more penetration and imaging depth <i>in vivo</i> than GCaMP. Use of red fluorescent indicators also avoids the photodamage caused by blue excitation light.<a class="footnote-ref" id="fnref:27" href="#fn:27"><sup>27</sup></a> Moreover, red fluorescent indicators allow for concurrent use of <a href="/facts/Optogenetics/RbYYcrr2">optogenetics</a>, which is difficult with GCaMP because the excitation wavelengths of GCaMP overlap with those of <a href="/facts/Channelrhodopsin/rg7KvAcU">channelrhodopsin-2</a> (ChR2).<a class="footnote-ref" id="fnref:28" href="#fn:28"><sup>28</sup></a><a class="footnote-ref" id="fnref:29" href="#fn:29"><sup>29</sup></a><a class="footnote-ref" id="fnref:30" href="#fn:30"><sup>30</sup></a> Simultaneous use of red and green GECIs can provide two-color visualization of different subcellular regions or cell populations.<a class="footnote-ref" id="fnref:31" href="#fn:31"><sup>31</sup></a><a class="footnote-ref" id="fnref:32" href="#fn:32"><sup>32</sup></a><a class="footnote-ref" id="fnref:33" href="#fn:33"><sup>33</sup></a> </p> <h2 id="applications-in-research">Applications in research</h2> <h3>Neuronal activity</h3> <p>In neurons, action potentials induce neurotransmitter release at <a href="/facts/Axon_terminals/QhUJg8SH">axon terminals</a> by opening <a href="/facts/Voltage-gated_calcium_channel/H9nAybJJ">voltage-gated Ca2+ channels</a>, allowing for Ca2+ influx. As a result, GCaMP is commonly used to measure increases in intracellular Ca2+ in neurons as a proxy for neuronal activity in multiple animal models, including <i><a href="/facts/Caenorhabditis_elegans/XJVJzPn2">Caenorhabditis elegans</a></i>, <a href="/facts/Zebrafish/Nxg1F1mG">zebrafish</a>, <i><a href="/facts/Drosophila/P4K7RkJl">Drosophila</a></i>, <a href="/facts/Rats/J2daVSTB">rats</a> and <a href="/facts/Mouse/6m1X7m0g">mice</a>.<a class="footnote-ref" id="fnref:34" href="#fn:34"><sup>34</sup></a> Recently, <a href="/facts/Genetically_encoded_voltage_indicator/pzvY57EK">genetically encoded voltage indicators</a> (GEVIs) have been developed alongside GECIs to more directly probe neuronal activity at the cellular level in these animal models.<a class="footnote-ref" id="fnref:35" href="#fn:35"><sup>35</sup></a> </p><p>GCaMP has played a vital role in establishing large-scale neural recordings in animals to investigate how activity patterns in neuronal networks influence behavior. For example, Nguyen et al. (2016) used GCaMP in whole-brain imaging during free movement of <i>C. elegans</i> to identify neurons and groups of neurons whose activity correlated with specific locomotor behaviors.<a class="footnote-ref" id="fnref:36" href="#fn:36"><sup>36</sup></a> </p><p>Muto et al. (2003) expressed GCaMP in zebrafish embryos to measure and map the coordinated activity of spinal <a href="/facts/Motor_neuron/LNqgmtYf">motor neurons</a> to different parts of the brain during the onset, propagation, and recovery of seizures induced by <a href="/facts/Pentylenetetrazol/YhtrPgEd">pentylenetetrazol</a>.<a class="footnote-ref" id="fnref:37" href="#fn:37"><sup>37</sup></a> GCaMP expression in zebrafish brains has also been used to study activation of neural circuits in cognitive processes like prey capture, impulse control, and attention.<a class="footnote-ref" id="fnref:38" href="#fn:38"><sup>38</sup></a><a class="footnote-ref" id="fnref:39" href="#fn:39"><sup>39</sup></a> </p><p>Additionally, researchers have used GCaMP to observe neuronal activity in mice by expressing it under control of the <a href="/facts/CD90/5PFk9ytS">Thy1</a> promoter, which is found in excitatory <a href="/facts/Pyramidal_cell/T8MTBq8b">pyramidal neurons</a>.<a class="footnote-ref" id="fnref:40" href="#fn:40"><sup>40</sup></a> For instance, integration of neurons into circuits during <a href="/facts/Motor_learning/jnm0vf1k">motor learning</a> has been tracked by using GCaMP to observe synchronized fluctuation patterns in Ca2+ levels.<a class="footnote-ref" id="fnref:41" href="#fn:41"><sup>41</sup></a><a class="footnote-ref" id="fnref:42" href="#fn:42"><sup>42</sup></a><a class="footnote-ref" id="fnref:43" href="#fn:43"><sup>43</sup></a> GCaMP has also been used to observe Ca2+ dynamics in subcellular compartments of mouse neurons: Cichon and Gan (2015) used GCaMP to show that neurons in the mouse <a href="/facts/Motor_cortex/oQ2w0g3S">motor cortex</a> exhibit <a href="/facts/N-Methyl-D-aspartic_acid/7jnfxMBU">NMDA</a>-driven increases in Ca2+ that are independent for each <a href="/facts/Dendritic_spine/wg54o3YT">dendritic spine</a>, thus showing that individual dendritic spines regulate <a href="/facts/Synaptic_plasticity/rdVFxItN">synaptic plasticity</a>.<a class="footnote-ref" id="fnref:44" href="#fn:44"><sup>44</sup></a> Finally, GCaMP has been used to identify activity patterns in specific regions of the mouse brain. For instance, Jones et al. (2018) used GCaMP6 in mice to measure neuronal activity in the <a href="/facts/Suprachiasmatic_nucleus/SILs86zl">suprachiasmatic nucleus</a> (SCN), the mammalian <a href="/facts/Circadian_rhythm/rwQh0ClJ">circadian</a> pacemaker, and showed that SCN neurons that produced <a href="/facts/Vasoactive_intestinal_peptide/KFsEElwE">vasoactive intestinal peptide</a> (VIP) exhibited daily activity rhythms <i>in vivo</i> that correlated with VIP release.<a class="footnote-ref" id="fnref:45" href="#fn:45"><sup>45</sup></a> </p><p>GCaMP has also been combined with <a href="/facts/Optical_fiber/5ruuIFbj">fiber</a> <a href="/facts/Photometry_(optics)/eo6J7qj3">photometry</a> to measure population-level Ca2+ changes within subpopulations of neurons in freely moving animals.<a class="footnote-ref" id="fnref:46" href="#fn:46"><sup>46</sup></a> For instance, Clarkson et al. (2017) used this method to show that neurons in the <a href="/facts/Arcuate_nucleus/lnbnpPtW">arcuate nucleus</a> of the <a href="/facts/Hypothalamus/lCkNt1bM">hypothalamus</a> synchronize to increases in Ca2+ immediately prior to pulses of <a href="/facts/Luteinizing_hormone/a6znte2S">luteinizing hormone</a> (LH).<a class="footnote-ref" id="fnref:47" href="#fn:47"><sup>47</sup></a> While GCaMP imaging with fiber photometry cannot track changes in Ca2+ levels within individual neurons, it provides greater <a href="/facts/Temporal_resolution/9wp61G97">temporal resolution</a> for large-scale changes.<a class="footnote-ref" id="fnref:48" href="#fn:48"><sup>48</sup></a> </p> <h3>Cardiac conduction</h3> <p>Ca2+ currents through <a href="/facts/Cardiac_muscle_cell/fE40oTQz">cardiomyocyte</a> <a href="/facts/Gap_junction/nhAEWww4">gap junctions</a> mediate synchronized contraction of cardiac tissue. As a result, GCaMP expression in cardiomyocytes, both <i>in vitro</i> and <i>in vivo</i>, has been used to study Ca2+-influx-dependent excitation and contraction in zebrafish and mice.<a class="footnote-ref" id="fnref:49" href="#fn:49"><sup>49</sup></a> For instance, Tallini et al. (2006) expressed GCaMP2 in mouse embryos to show that, at embryonic day 10.5, <a href="/facts/Electrical_conduction_system_of_the_heart/AouErvDx">electrical conduction</a> was rapid in the <a href="/facts/Atrium_(heart)/eYNg8Vw2">atria</a> and <a href="/facts/Ventricle_(heart)/FCzV1xm7">ventricles</a> but slow in the <a href="/facts/Atrioventricular_canal/vpCmq28M">atrioventricular canal</a>.<a class="footnote-ref" id="fnref:50" href="#fn:50"><sup>50</sup></a> Chi et al. (2008) used a transgenic cardiac-specific GCaMP zebrafish line to image cardiomyocyte activation throughout the cardiac cycle; from their results, they characterized four developmental stages of the zebrafish cardiac conduction system and identified 17 novel <a href="/facts/Mutation/Ee4NnWbY">mutations</a> affecting cardiac conduction.<a class="footnote-ref" id="fnref:51" href="#fn:51"><sup>51</sup></a> However, uncontrolled expression of GCaMP leads to cardiac <a href="/facts/Hypertrophy/4JolPfnS">hypertrophy</a> due to overexpression of the calmodulin motif, which interferes with intracellular calcium signaling. As a result, experiments using cardiac tissue should carefully control the level of GCaMP expression.<a class="footnote-ref" id="fnref:52" href="#fn:52"><sup>52</sup></a> </p> <h3>Signaling pathway activation</h3> <p>Since Ca2+ is a common second messenger, GCaMP has been used to monitor the activation of signaling pathways. For instance, Bonder and McCarthy (2014) used GCaMP to show that <a href="/facts/Astrocyte/PBUuHKzS">astrocytic</a> <a href="/facts/G_protein-coupled_receptor/0arUMkQc">G-protein coupled receptor</a> (GPCR) signaling and subsequent Ca2+ release was not responsible for neurovascular coupling, the process by which changes in neuronal activity lead to changes in local blood flow.<a class="footnote-ref" id="fnref:53" href="#fn:53"><sup>53</sup></a> Similarly, Greer and Bear et al. (2016) used GCaMP to characterize the dynamics of Ca2+ influx in necklace <a href="/facts/Olfaction/t6ytFklU">olfactory</a> neuron signaling, which uses <a href="/facts/Transmembrane_protein/0vQH5HrM">transmembrane</a> <a href="/facts/Membrane-spanning_4A/nc8v2QRC">MS4A</a> proteins as <a href="/facts/Chemoreceptor/KC6IDxzf">chemoreceptors</a>.<a class="footnote-ref" id="fnref:54" href="#fn:54"><sup>54</sup></a> </p> <h2 id="see-also">See also</h2> <ul><li><a href="/facts/Calcium_imaging/3Y85smYK">Calcium imaging</a></li> <li><a href="/facts/Calcium_in_biology/wgUxKej5">Calcium in biology</a></li> <li><a href="/facts/Calmodulin/CbEnEYHE">Calmodulin</a></li> <li><a href="/facts/Cameleon_(protein)/hHqYSEkH">Cameleon (protein)</a></li> <li><a href="/facts/Green_fluorescent_protein/6nWDMhSC">Green fluorescent protein</a></li> <li><a href="/facts/Myosin_light-chain_kinase/cgtPHhMG">Myosin light-chain kinase</a></li></ul> <h2 id="references">References</h2> <ol> <li id="fn:1"><p>Nakai J, Ohkura M, Imoto K (February 2001). "A high signal-to-noise Ca(2+) probe composed of a single green fluorescent protein". Nature Biotechnology. 19 (2): 137–41. doi:10.1038/84397. PMID 11175727. S2CID 30254550. <a href="/wiki/Doi_(identifier)" target="_blank">/wiki/Doi_(identifier)</a> <a href="#fnref:1" class="footnote-back-ref">↩</a></p></li> <li id="fn:2"><p>Chen TW, Wardill TJ, Sun Y, Pulver SR, Renninger SL, Baohan A, et al. (July 2013). "Ultrasensitive fluorescent proteins for imaging neuronal activity". Nature. 499 (7458): 295–300. Bibcode:2013Natur.499..295C. doi:10.1038/nature12354. PMC 3777791. PMID 23868258. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3777791" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3777791</a> <a href="#fnref:2" class="footnote-back-ref">↩</a></p></li> <li id="fn:3"><p>Barnett LM, Hughes TE, Drobizhev M (2017-02-09). "Deciphering the molecular mechanism responsible for GCaMP6m's Ca2+-dependent change in fluorescence". PLOS ONE. 12 (2): e0170934. Bibcode:2017PLoSO..1270934B. doi:10.1371/journal.pone.0170934. PMC 5300113. PMID 28182677. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5300113" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5300113</a> <a href="#fnref:3" class="footnote-back-ref">↩</a></p></li> <li id="fn:4"><p>Chen TW, Wardill TJ, Sun Y, Pulver SR, Renninger SL, Baohan A, et al. (July 2013). "Ultrasensitive fluorescent proteins for imaging neuronal activity". Nature. 499 (7458): 295–300. Bibcode:2013Natur.499..295C. doi:10.1038/nature12354. PMC 3777791. PMID 23868258. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3777791" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3777791</a> <a href="#fnref:4" class="footnote-back-ref">↩</a></p></li> <li id="fn:5"><p>Whitaker M (2010-01-01). "Genetically encoded probes for measurement of intracellular calcium". Calcium in Living Cells. Methods in Cell Biology. Vol. 99. pp. 153–82. doi:10.1016/B978-0-12-374841-6.00006-2. ISBN 9780123748416. PMC 3292878. PMID 21035686. <a href="9780123748416" target="_blank">9780123748416</a> <a href="#fnref:5" class="footnote-back-ref">↩</a></p></li> <li id="fn:6"><p>Ji G, Feldman ME, Deng KY, Greene KS, Wilson J, Lee JC, et al. (May 2004). "Ca2+-sensing transgenic mice: postsynaptic signaling in smooth muscle". The Journal of Biological Chemistry. 279 (20): 21461–8. doi:10.1074/jbc.M401084200. PMID 14990564. S2CID 9532711. <a href="https://doi.org/10.1074%2Fjbc.M401084200" target="_blank">https://doi.org/10.1074%2Fjbc.M401084200</a> <a href="#fnref:6" class="footnote-back-ref">↩</a></p></li> <li id="fn:7"><p>Akerboom J, Rivera JD, Guilbe MM, Malavé EC, Hernandez HH, Tian L, et al. (March 2009). "Crystal structures of the GCaMP calcium sensor reveal the mechanism of fluorescence signal change and aid rational design". The Journal of Biological Chemistry. 284 (10): 6455–64. doi:10.1074/jbc.M807657200. PMC 2649101. PMID 19098007. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2649101" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2649101</a> <a href="#fnref:7" class="footnote-back-ref">↩</a></p></li> <li id="fn:8"><p>Wang Q, Shui B, Kotlikoff MI, Sondermann H (December 2008). "Structural basis for calcium sensing by GCaMP2". Structure. 16 (12): 1817–27. doi:10.1016/j.str.2008.10.008. PMC 2614139. PMID 19081058. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2614139" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2614139</a> <a href="#fnref:8" class="footnote-back-ref">↩</a></p></li> <li id="fn:9"><p>Nakai J, Ohkura M, Imoto K (February 2001). "A high signal-to-noise Ca(2+) probe composed of a single green fluorescent protein". Nature Biotechnology. 19 (2): 137–41. doi:10.1038/84397. PMID 11175727. S2CID 30254550. <a href="/wiki/Doi_(identifier)" target="_blank">/wiki/Doi_(identifier)</a> <a href="#fnref:9" class="footnote-back-ref">↩</a></p></li> <li id="fn:10"><p>Ji G, Feldman ME, Deng KY, Greene KS, Wilson J, Lee JC, et al. (May 2004). "Ca2+-sensing transgenic mice: postsynaptic signaling in smooth muscle". The Journal of Biological Chemistry. 279 (20): 21461–8. doi:10.1074/jbc.M401084200. PMID 14990564. S2CID 9532711. <a href="https://doi.org/10.1074%2Fjbc.M401084200" target="_blank">https://doi.org/10.1074%2Fjbc.M401084200</a> <a href="#fnref:10" class="footnote-back-ref">↩</a></p></li> <li id="fn:11"><p>Nakai J, Ohkura M, Imoto K (February 2001). "A high signal-to-noise Ca(2+) probe composed of a single green fluorescent protein". Nature Biotechnology. 19 (2): 137–41. doi:10.1038/84397. PMID 11175727. S2CID 30254550. <a href="/wiki/Doi_(identifier)" target="_blank">/wiki/Doi_(identifier)</a> <a href="#fnref:11" class="footnote-back-ref">↩</a></p></li> <li id="fn:12"><p>Tallini YN, Ohkura M, Choi BR, Ji G, Imoto K, Doran R, et al. (March 2006). "Imaging cellular signals in the heart in vivo: Cardiac expression of the high-signal Ca2+ indicator GCaMP2". Proceedings of the National Academy of Sciences of the United States of America. 103 (12): 4753–8. Bibcode:2006PNAS..103.4753T. doi:10.1073/pnas.0509378103. PMC 1450242. PMID 16537386. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1450242" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1450242</a> <a href="#fnref:12" class="footnote-back-ref">↩</a></p></li> <li id="fn:13"><p>Tallini YN, Ohkura M, Choi BR, Ji G, Imoto K, Doran R, et al. (March 2006). "Imaging cellular signals in the heart in vivo: Cardiac expression of the high-signal Ca2+ indicator GCaMP2". 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