Discrete-State Stochastic Models of Calcium-Regulated Calcium Influx and Subspace Dynamics Are Not Well-Approximated by ODEs That Neglect Concentration Fluctuations

<table>Percentage small system deviation (<svg height="11.425" id="M218" style="vertical-align:-0.0pt" version="1.1" viewbox="0 0 11.025 11.425" width="11.025" xmlns="http://www.w3.org/2000/svg" xmlns:xlink="http://www.w3.org/1999/xlink">
<g transform="matrix(.017,-0,0,-.017,.062,11.363)"><path d="M600 0h-557v24l268 633l28 8l261 -641v-24zM497 50l-194 489l-196 -489h390z" id="x394"></path></g>
</svg>, (<a href="https://static.hindawi.com/articles/cmmm/volume-2012/897371/figures/#EEq31">32</a>)) as a function of unitary subspace volume <svg height="11.9625" id="M219" style="vertical-align:-3.3907pt" version="1.1" viewbox="0 0 14.6125 11.9625" width="14.6125" xmlns="http://www.w3.org/2000/svg" xmlns:xlink="http://www.w3.org/1999/xlink">
<g transform="matrix(.017,-0,0,-.017,.062,7.675)"><path d="M457 332q0 -81 -41 -161.5t-105.5 -131.5t-129.5 -51q-46 0 -79 30.5t-33 86.5q0 18 7 51q18 95 46 187q6 19 6 33q0 7 -7 7q-24 0 -78 -64l-20 23q32 48 73 77t78 29q33 0 33 -46q0 -38 -10 -70q-28 -92 -39 -152q-7 -38 -7 -57q0 -78 69 -78q68 0 118 75.5t50 194.5
q0 43 -12 57q-11 12 -11 24q0 19 15 35.5t34 16.5q18 0 30.5 -34.5t12.5 -81.5z" id="x1D463"></path></g>
<g transform="matrix(.012,-0,0,-.012,8.225,11.762)"><path d="M241 635q53 0 94 -28.5t63.5 -76t33.5 -102.5t11 -116q0 -58 -11 -112.5t-34 -103.5t-63.5 -78.5t-94.5 -29.5t-95 28t-64.5 75t-34.5 102.5t-11 118.5q0 58 11.5 112.5t34.5 103t64.5 78t95.5 29.5zM238 602q-32 0 -55.5 -25t-35.5 -68t-17.5 -91t-5.5 -105
q0 -76 10 -138.5t37 -107.5t69 -45q32 0 55.5 25t35.5 68.5t17.5 91.5t5.5 105t-5.5 105.5t-18 92t-36 68t-56.5 24.5z" id="x30"></path></g>
</svg> and influx parameter <svg height="11.825" id="M220" style="vertical-align:-3.27605pt" version="1.1" viewbox="0 0 14.6375 11.825" width="14.6375" xmlns="http://www.w3.org/2000/svg" xmlns:xlink="http://www.w3.org/1999/xlink">
<g transform="matrix(.017,-0,0,-.017,.062,7.675)"><path d="M383 397q0 -32 -35 -49q-12 -6 -23 8q-37 45 -84 45t-90 -71q-40 -65 -40 -167q0 -57 22 -86t59 -29q38 0 81.5 24.5t69.5 51.5l16 -21q-44 -53 -104 -84t-109 -31q-56 0 -89.5 41t-33.5 117q0 61 30 124t79 105q33 28 81 50.5t86 22.5q34 0 59 -15.5t25 -35.5z" id="x1D450"></path></g>
<g transform="matrix(.012,-0,0,-.012,6.962,11.762)"><path d="M471 153q-22 -15 -61 -13q-25 31 -45.5 49.5t-56.5 41.5q4 -71 28 -134q-17 -33 -42 -46q-24 12 -42 46q24 63 28 134q-36 -23 -56.5 -41.5t-45.5 -49.5q-36 -2 -61 13q0 28 19 59q65 10 130 43q-65 33 -130 43q-19 31 -19 59q22 15 61 13q25 -31 45.5 -49.5t56.5 -41.5
q-4 71 -28 134q17 33 42 46q24 -12 42 -46q-24 -63 -28 -134q36 23 56.5 41.5t45.5 49.5q36 2 61 -13q0 -28 -19 -59q-65 -10 -130 -43q65 -33 130 -43q19 -31 19 -59z" id="x2217"></path></g>
</svg> for a single calcium-activated channel (<svg height="11.125" id="M221" style="vertical-align:-0.1638pt" version="1.1" viewbox="0 0 36.325001 11.125" width="36.325001" xmlns="http://www.w3.org/2000/svg" xmlns:xlink="http://www.w3.org/1999/xlink">
<g transform="matrix(.017,-0,0,-.017,.062,10.862)"><path d="M484 406q0 -21 -22 -38q-10 -7 -18 -1q-15 11 -30 11q-30 0 -77.5 -37t-74.5 -67l79 -168q11 -23 19.5 -34.5t13 -14t10.5 -2.5q9 0 30 17.5t40 42.5l17 -23q-31 -45 -57.5 -69.5t-40.5 -29.5t-31 -5q-18 0 -32 13.5t-35 55.5q-34 71 -69 160q-36 -32 -59 -56
q-12 -27 -36 -158q-44 -7 -77 -15l-5 7l82 349q6 25 -2 25q-16 0 -72 -41l-14 22q44 41 89 69.5t66 28.5q19 0 19 -32q0 -16 -6 -43l-35 -160l146 143q94 92 136 92q20 0 33 -12t13 -30z" id="x1D705"></path></g><g transform="matrix(.017,-0,0,-.017,13.39,10.862)"><path d="M535 323h-483v50h483v-50zM535 138h-483v50h483v-50z" id="x3D"></path></g><g transform="matrix(.017,-0,0,-.017,28.093,10.862)"><path d="M412 140l28 -9q0 -2 -35 -131h-373v23q112 112 161 170q59 70 92 127t33 115q0 63 -31 98t-86 35q-75 0 -137 -93l-22 20l57 81q55 59 135 59q69 0 118.5 -46.5t49.5 -122.5q0 -62 -29.5 -114t-102.5 -130l-141 -149h186q42 0 58.5 10.5t38.5 56.5z" id="x32"></path></g>
</svg> <i>μ</i>M, <svg height="14.3125" id="M222" style="vertical-align:-0.1638pt" version="1.1" viewbox="0 0 72.212502 14.3125" width="72.212502" xmlns="http://www.w3.org/2000/svg" xmlns:xlink="http://www.w3.org/1999/xlink">
<g transform="matrix(.017,-0,0,-.017,.062,14.05)"><path d="M480 416q0 -21 -18 -41q-9 -11 -17 -7q-20 9 -42 9q-62 0 -140 -78q23 -69 88 -192q17 -31 27 -42t20 -11q16 0 62 46l17 -20q-64 -92 -119 -92q-35 0 -70 66q-41 73 -84 187q-36 -30 -62 -61q-27 -115 -35 -172q-41 -8 -78 -20l-6 6l140 612q7 28 0.5 34t-37.5 7l-34 1
l5 26q38 4 74 13.5t57 17t25 7.5q12 0 4 -32l-104 -443h2q35 38 97 93q39 35 65.5 56t62 41.5t58.5 20.5q19 0 30.5 -10t11.5 -22z" id="x1D458"></path></g>
<g transform="matrix(.012,-0,0,-.012,8.612,5.887)"><path d="M535 230h-212v-233h-58v233h-213v50h213v210h58v-210h212v-50z" id="x2B"></path></g>
<g transform="matrix(.017,-0,0,-.017,20.938,14.05)"><path d="M535 323h-483v50h483v-50zM535 138h-483v50h483v-50z" id="x3D"></path></g><g transform="matrix(.017,-0,0,-.017,35.641,14.05)"><path d="M241 635q53 0 94 -28.5t63.5 -76t33.5 -102.5t11 -116q0 -58 -11 -112.5t-34 -103.5t-63.5 -78.5t-94.5 -29.5t-95 28t-64.5 75t-34.5 102.5t-11 118.5q0 58 11.5 112.5t34.5 103t64.5 78t95.5 29.5zM238 602q-32 0 -55.5 -25t-35.5 -68t-17.5 -91t-5.5 -105
q0 -76 10 -138.5t37 -107.5t69 -45q32 0 55.5 25t35.5 68.5t17.5 91.5t5.5 105t-5.5 105.5t-18 92t-36 68t-56.5 24.5z" id="x30"></path></g><g transform="matrix(.017,-0,0,-.017,43.801,14.05)"><path d="M113 -12q-24 0 -39.5 16t-15.5 42q0 24 16 40.5t40 16.5t40 -16.5t16 -40.5q0 -26 -16 -42t-41 -16z" id="x2E"></path></g><g transform="matrix(.017,-0,0,-.017,47.677,14.05)"><path d="M241 635q53 0 94 -28.5t63.5 -76t33.5 -102.5t11 -116q0 -58 -11 -112.5t-34 -103.5t-63.5 -78.5t-94.5 -29.5t-95 28t-64.5 75t-34.5 102.5t-11 118.5q0 58 11.5 112.5t34.5 103t64.5 78t95.5 29.5zM238 602q-32 0 -55.5 -25t-35.5 -68t-17.5 -91t-5.5 -105
q0 -76 10 -138.5t37 -107.5t69 -45q32 0 55.5 25t35.5 68.5t17.5 91.5t5.5 105t-5.5 105.5t-18 92t-36 68t-56.5 24.5z" id="x30"></path></g><g transform="matrix(.017,-0,0,-.017,55.836,14.05)"><path d="M241 635q53 0 94 -28.5t63.5 -76t33.5 -102.5t11 -116q0 -58 -11 -112.5t-34 -103.5t-63.5 -78.5t-94.5 -29.5t-95 28t-64.5 75t-34.5 102.5t-11 118.5q0 58 11.5 112.5t34.5 103t64.5 78t95.5 29.5zM238 602q-32 0 -55.5 -25t-35.5 -68t-17.5 -91t-5.5 -105
q0 -76 10 -138.5t37 -107.5t69 -45q32 0 55.5 25t35.5 68.5t17.5 91.5t5.5 105t-5.5 105.5t-18 92t-36 68t-56.5 24.5z" id="x30"></path></g><g transform="matrix(.017,-0,0,-.017,63.995,14.05)"><path d="M153 550l-26 -186q79 31 111 31q90 0 141.5 -51t51.5 -119q0 -93 -89 -166q-85 -69 -173 -71q-32 0 -61.5 11.5t-41.5 23.5q-18 17 -17 34q2 16 22 33q14 9 26 -1q61 -50 124 -50q60 0 93 43.5t33 104.5q0 69 -41.5 110t-121.5 41q-53 0 -102 -20l38 305h286l6 -8
l-26 -65h-233z" id="x35"></path></g>
</svg> <i>μ</i>M<sup>−2</sup> ms<sup>−1</sup>) and calcium-inactivated channel (<svg height="11.225" id="M223" style="vertical-align:-0.1638pt" version="1.1" viewbox="0 0 56.525002 11.225" width="56.525002" xmlns="http://www.w3.org/2000/svg" xmlns:xlink="http://www.w3.org/1999/xlink">
<g transform="matrix(.017,-0,0,-.017,.062,10.963)"><path d="M484 406q0 -21 -22 -38q-10 -7 -18 -1q-15 11 -30 11q-30 0 -77.5 -37t-74.5 -67l79 -168q11 -23 19.5 -34.5t13 -14t10.5 -2.5q9 0 30 17.5t40 42.5l17 -23q-31 -45 -57.5 -69.5t-40.5 -29.5t-31 -5q-18 0 -32 13.5t-35 55.5q-34 71 -69 160q-36 -32 -59 -56
q-12 -27 -36 -158q-44 -7 -77 -15l-5 7l82 349q6 25 -2 25q-16 0 -72 -41l-14 22q44 41 89 69.5t66 28.5q19 0 19 -32q0 -16 -6 -43l-35 -160l146 143q94 92 136 92q20 0 33 -12t13 -30z" id="x1D705"></path></g><g transform="matrix(.017,-0,0,-.017,13.39,10.963)"><path d="M535 323h-483v50h483v-50zM535 138h-483v50h483v-50z" id="x3D"></path></g><g transform="matrix(.017,-0,0,-.017,28.093,10.963)"><path d="M241 635q53 0 94 -28.5t63.5 -76t33.5 -102.5t11 -116q0 -58 -11 -112.5t-34 -103.5t-63.5 -78.5t-94.5 -29.5t-95 28t-64.5 75t-34.5 102.5t-11 118.5q0 58 11.5 112.5t34.5 103t64.5 78t95.5 29.5zM238 602q-32 0 -55.5 -25t-35.5 -68t-17.5 -91t-5.5 -105
q0 -76 10 -138.5t37 -107.5t69 -45q32 0 55.5 25t35.5 68.5t17.5 91.5t5.5 105t-5.5 105.5t-18 92t-36 68t-56.5 24.5z" id="x30"></path></g><g transform="matrix(.017,-0,0,-.017,36.253,10.963)"><path d="M113 -12q-24 0 -39.5 16t-15.5 42q0 24 16 40.5t40 16.5t40 -16.5t16 -40.5q0 -26 -16 -42t-41 -16z" id="x2E"></path></g><g transform="matrix(.017,-0,0,-.017,40.129,10.963)"><path d="M137 343l67 33q37 17 63 17q79 0 129.5 -53t50.5 -131q0 -92 -58 -156.5t-147 -64.5t-147 68t-58 182q0 63 17 119t43 95.5t61.5 72t69 52t67.5 31.5q62 22 128 33l6 -32q-56 -11 -108 -35q-149 -71 -184 -231zM227 337q-47 0 -95 -27q-6 -23 -6 -70q0 -93 36 -155.5
t96 -62.5q53 0 78 45.5t25 105.5q0 68 -35 116t-99 48z" id="x36"></path></g><g transform="matrix(.017,-0,0,-.017,48.288,10.963)"><path d="M285 378v-2q65 -13 102 -54.5t37 -97.5q0 -57 -30.5 -104.5t-74 -75t-85.5 -42t-72 -14.5q-31 0 -59.5 11t-40.5 23q-19 18 -16 36q1 16 23 33q13 10 24 0q58 -51 124 -51q55 0 88 40t33 112q0 64 -39 96.5t-88 32.5q-29 0 -64 -11l-6 29q77 25 118 57.5t41 84.5
q0 45 -26.5 69.5t-68.5 24.5q-67 0 -120 -79l-20 20l43 63q51 56 127 56h1q66 0 107 -37t41 -95q0 -42 -31 -71q-22 -23 -68 -54z" id="x33"></path></g>
</svg> <i>μ</i>M, <svg height="14.3125" id="M224" style="vertical-align:-0.1638pt" version="1.1" viewbox="0 0 64.0625 14.3125" width="64.0625" xmlns="http://www.w3.org/2000/svg" xmlns:xlink="http://www.w3.org/1999/xlink">
<g transform="matrix(.017,-0,0,-.017,.062,14.05)"><path d="M480 416q0 -21 -18 -41q-9 -11 -17 -7q-20 9 -42 9q-62 0 -140 -78q23 -69 88 -192q17 -31 27 -42t20 -11q16 0 62 46l17 -20q-64 -92 -119 -92q-35 0 -70 66q-41 73 -84 187q-36 -30 -62 -61q-27 -115 -35 -172q-41 -8 -78 -20l-6 6l140 612q7 28 0.5 34t-37.5 7l-34 1
l5 26q38 4 74 13.5t57 17t25 7.5q12 0 4 -32l-104 -443h2q35 38 97 93q39 35 65.5 56t62 41.5t58.5 20.5q19 0 30.5 -10t11.5 -22z" id="x1D458"></path></g>
<g transform="matrix(.012,-0,0,-.012,8.612,5.887)"><path d="M535 230h-212v-233h-58v233h-213v50h213v210h58v-210h212v-50z" id="x2B"></path></g>
<g transform="matrix(.017,-0,0,-.017,20.938,14.05)"><path d="M535 323h-483v50h483v-50zM535 138h-483v50h483v-50z" id="x3D"></path></g><g transform="matrix(.017,-0,0,-.017,35.641,14.05)"><path d="M241 635q53 0 94 -28.5t63.5 -76t33.5 -102.5t11 -116q0 -58 -11 -112.5t-34 -103.5t-63.5 -78.5t-94.5 -29.5t-95 28t-64.5 75t-34.5 102.5t-11 118.5q0 58 11.5 112.5t34.5 103t64.5 78t95.5 29.5zM238 602q-32 0 -55.5 -25t-35.5 -68t-17.5 -91t-5.5 -105
q0 -76 10 -138.5t37 -107.5t69 -45q32 0 55.5 25t35.5 68.5t17.5 91.5t5.5 105t-5.5 105.5t-18 92t-36 68t-56.5 24.5z" id="x30"></path></g><g transform="matrix(.017,-0,0,-.017,43.801,14.05)"><path d="M113 -12q-24 0 -39.5 16t-15.5 42q0 24 16 40.5t40 16.5t40 -16.5t16 -40.5q0 -26 -16 -42t-41 -16z" id="x2E"></path></g><g transform="matrix(.017,-0,0,-.017,47.677,14.05)"><path d="M241 635q53 0 94 -28.5t63.5 -76t33.5 -102.5t11 -116q0 -58 -11 -112.5t-34 -103.5t-63.5 -78.5t-94.5 -29.5t-95 28t-64.5 75t-34.5 102.5t-11 118.5q0 58 11.5 112.5t34.5 103t64.5 78t95.5 29.5zM238 602q-32 0 -55.5 -25t-35.5 -68t-17.5 -91t-5.5 -105
q0 -76 10 -138.5t37 -107.5t69 -45q32 0 55.5 25t35.5 68.5t17.5 91.5t5.5 105t-5.5 105.5t-18 92t-36 68t-56.5 24.5z" id="x30"></path></g><g transform="matrix(.017,-0,0,-.017,55.836,14.05)"><path d="M153 550l-26 -186q79 31 111 31q90 0 141.5 -51t51.5 -119q0 -93 -89 -166q-85 -69 -173 -71q-32 0 -61.5 11.5t-41.5 23.5q-18 17 -17 34q2 16 22 33q14 9 26 -1q61 -50 124 -50q60 0 93 43.5t33 104.5q0 69 -41.5 110t-121.5 41q-53 0 -102 -20l38 305h286l6 -8
l-26 -65h-233z" id="x35"></path></g>
</svg> <i>μ</i>M<sup>−2</sup> ms<sup>−1</sup>).</table>

Computational and Mathematical Methods in Medicine

fig5

Figure 5

Figure 5: Discrete-State Stochastic Models of Calcium-Regulated Calcium Influx and Subspace Dynamics Are Not Well-Approximated by ODEs That Neglect Concentration Fluctuations 

Figure 5 | Discrete-State Stochastic Models of Calcium-Regulated Calcium Influx and Subspace Dynamics Are Not Well-Approximated by ODEs That Neglect Concentration Fluctuations 