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 <o:shapedefaults v:ext="edit" spidmax="1026"/>
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 <o:shapelayout v:ext="edit">
  <o:idmap v:ext="edit" data="1"/>
 </o:shapelayout></xml><![endif]-->
</head>

<body lang=DE link=blue vlink=purple style='tab-interval:35.4pt'>

<div class=WordSection1>

<p class=MsoNormal style='margin-bottom:0cm;margin-bottom:.0001pt;line-height:
normal;text-autospace:none'><span lang=EN-US style='font-family:"Courier New";
mso-ansi-language:EN-US'>---------------------</span><span lang=EN-US
style='mso-ansi-language:EN-US'><o:p></o:p></span></p>

<p class=MsoNormal style='margin-bottom:0cm;margin-bottom:.0001pt;line-height:
normal;text-autospace:none'><span lang=EN-US style='font-family:"Courier New";
mso-ansi-language:EN-US'>1. Model information:</span><span lang=EN-US
style='mso-ansi-language:EN-US'><o:p></o:p></span></p>

<p class=MsoNormal style='margin-bottom:0cm;margin-bottom:.0001pt;line-height:
normal;text-autospace:none'><span lang=EN-US style='font-family:"Courier New";
mso-ansi-language:EN-US'>---------------------</span><span lang=EN-US
style='mso-ansi-language:EN-US'><o:p></o:p></span></p>

<p class=MsoNormal style='margin-bottom:0cm;margin-bottom:.0001pt;line-height:
normal;text-autospace:none'><span lang=EN-US style='font-family:"Courier New";
mso-ansi-language:EN-US'>This is the readme for the model associated with the
paper:</span><span lang=EN-US style='mso-ansi-language:EN-US'><o:p></o:p></span></p>

<p class=MsoNormal style='margin-bottom:0cm;margin-bottom:.0001pt;line-height:
normal;text-autospace:none'><span lang=EN-US style='font-family:"Courier New";
mso-ansi-language:EN-US'>&nbsp;</span><span lang=EN-US style='mso-ansi-language:
EN-US'><o:p></o:p></span></p>

<p class=MsoNormal style='margin-bottom:0cm;margin-bottom:.0001pt;line-height:
normal;text-autospace:none'><span class=SpellE><span lang=EN-US
style='font-family:"Courier New";mso-ansi-language:EN-US'>Neumaier</span></span><span
lang=EN-US style='font-family:"Courier New";mso-ansi-language:EN-US'> F, <span
class=SpellE>Apldogan</span> S, <span class=SpellE>Hescheler</span> J and
Schneider T (2020) Zn<sup>2+</sup>-induced changes in Ca<sub>v</sub>2.3 channel
function: An electrophysiological and modeling study. <i style='mso-bidi-font-style:
normal'>J. Gen. Physiol. </i>(<a href="https://doi.org/10.1085/jgp.202012585">https://doi.org/10.1085/jgp.202012585</a>)&nbsp;</span><span
lang=EN-US style='mso-ansi-language:EN-US'><o:p></o:p></span></p>

<p class=MsoNormal style='margin-bottom:0cm;margin-bottom:.0001pt;line-height:
normal;text-autospace:none'><span lang=EN-US style='mso-ansi-language:EN-US'>&nbsp;<o:p></o:p></span></p>

<p class=MsoNormal style='margin-bottom:0cm;margin-bottom:.0001pt;line-height:
normal;text-autospace:none'><span lang=EN-US style='font-family:"Courier New";
mso-ansi-language:EN-US'>Model information:</span><span lang=EN-US
style='mso-ansi-language:EN-US'><o:p></o:p></span></p>

<p class=MsoNormal style='margin-bottom:0cm;margin-bottom:.0001pt;line-height:
normal;text-autospace:none'><span lang=EN-US style='font-family:"Courier New";
mso-ansi-language:EN-US'>------------------</span><span lang=EN-US
style='mso-ansi-language:EN-US'><o:p></o:p></span></p>

<p class=MsoNormal style='margin-bottom:0cm;margin-bottom:.0001pt;text-align:
justify;line-height:normal;text-autospace:none'><span lang=EN-US
style='font-family:"Courier New";mso-ansi-language:EN-US'>The state diagram for
the Ca<sub>v</sub>2.3 channel model in the absence of trace metal ions, which
was developed based on channel structure, previous modeling studies and the
ability to fit the data, is shown below (see also Fig. 15 in the accompanying
paper). Horizontal transitions are voltage-dependent and correspond to movement
of the four non-identical voltage-sensors and pore opening or closing
respectively. Activation of two voltage-sensors (1 and 2) is obligatory for
channel opening, giving rise to a total of 4 open states. Vertical transitions
are voltage-independent and correspond to entry into and return from fast and
slow inactivated states. The rates for voltage-dependent transitions were
expressed in terms of the transition-state theory, and the parameters optimized
by fitting the model to macroscopic currents recorded with various
electrophysiological protocols (see below). The effects of Zn<sup>2+</sup> were
implemented by assuming that Zn<sup>2+</sup> binding to a first site (<span
class=SpellE>K<sub>Zn</sub></span>=0.003 <span class=SpellE>mM</span>) leads to
electrostatic modification and mechanical slowing of one of the voltage-sensors
while Zn<sup>2+</sup>-binding to a second, intra-pore site (<span class=SpellE>K<sub>Zn</sub></span>=0.1
<span class=SpellE>mM</span>) blocks the channel and modifies the opening and
closing transitions (for details see the accompanying paper).</span><span
lang=EN-US style='mso-ansi-language:EN-US'><o:p></o:p></span></p>

<p class=MsoNormal style='margin-bottom:0cm;margin-bottom:.0001pt;text-align:
justify;line-height:normal;text-autospace:none'><span lang=EN-US
style='mso-ansi-language:EN-US'>&nbsp;<o:p></o:p></span></p>

<p class=MsoNormal style='margin-bottom:0cm;margin-bottom:.0001pt;text-align:
justify;line-height:normal;text-autospace:none'><span style='mso-no-proof:yes'><img
border=0 width=790 height=423 id="_x0000_i1026"
src="readme-Dateien/image001.jpg"
alt="Beschreibung: Beschreibung: Beschreibung: Beschreibung: Beschreibung: C:\Users\Felix\Dropbox\5. MANUSCRIPTS\Eigene\Zn Effects and Model Neu\Model (Site 1+2)\New folder\Final_Revised\Cav23\readme-Dateien\image001.jpg"></span></p>

<p class=MsoNormal style='margin-bottom:0cm;margin-bottom:.0001pt;text-align:
justify;line-height:normal;text-autospace:none'><span lang=EN-US
style='mso-ansi-language:EN-US'>&nbsp;<o:p></o:p></span></p>

<p class=MsoNormal style='margin-bottom:0cm;margin-bottom:.0001pt;text-align:
justify;line-height:normal;text-autospace:none'><span lang=EN-US
style='mso-ansi-language:EN-US'>&nbsp;<o:p></o:p></span></p>

<p class=MsoNormal style='margin-bottom:0cm;margin-bottom:.0001pt;text-align:
justify;line-height:normal;text-autospace:none'><span lang=EN-US
style='font-family:"Courier New";mso-ansi-language:EN-US'>Experimental and
modeling conditions:</span><span lang=EN-US style='mso-ansi-language:EN-US'><o:p></o:p></span></p>

<p class=MsoNormal style='margin-bottom:0cm;margin-bottom:.0001pt;text-align:
justify;line-height:normal;text-autospace:none'><span lang=EN-US
style='font-family:"Courier New";mso-ansi-language:EN-US'>------------------------</span><span
lang=EN-US style='mso-ansi-language:EN-US'><o:p></o:p></span></p>

<p class=MsoNormal style='margin-bottom:0cm;margin-bottom:.0001pt;text-align:
justify;line-height:normal;text-autospace:none'><span lang=EN-US
style='font-family:"Courier New";mso-ansi-language:EN-US'>As a basis for model
development, whole-cell patch-clamp recordings were performed in HEK-293 cells
stably transfected with human Ca<sub>v</sub>2.3+&#946;<sub>3</sub> channel
subunits. All recordings were performed at room temperature and with
near-physiological extracellular solutions that contained 4 <span class=SpellE>mM</span>
free Ca<sup>2+</sup> for ionic currents or 4 <span class=SpellE>mM</span> free
Mg<sup>2+</sup> and 0.1 <span class=SpellE>mM</span> free La<sup>3+</sup> for
gating currents. The complete data set used for fitting included gating
currents recorded at 15 different test potentials, long (400 <span
class=SpellE>ms</span>) and short (25 <span class=SpellE>ms</span>) IV-currents
recorded at 10 and 15 different test potentials respectively, IIV-currents
recorded at 13 different test potentials and PPI-currents recorded at 14
different test potentials (for details on the voltage protocols see the
accompanying paper and the simulations below). Parameter optimization and
simulations were performed with an <i style='mso-bidi-font-style:normal'>in <span
class=SpellE>silico</span></i> one-compartmental model of a HEK293 cell with
diameter and length 21.851 µm, which corresponds to a sphere with a surface
area of 1500 µm<sup>2</sup>. Default temperature, specific membrane capacitance
and cytoplasmic resistivity were 22°C, 1 µF/cm<sup>2</sup> and 60 &#8486;*cm
respectively. <span style='mso-spacerun:yes'> </span></span><span lang=EN-US
style='mso-ansi-language:EN-US'><o:p></o:p></span></p>

<p class=MsoNormal style='margin-bottom:0cm;margin-bottom:.0001pt;line-height:
normal;text-autospace:none'><span lang=EN-US style='font-family:"Courier New";
mso-ansi-language:EN-US'>&nbsp;&nbsp;</span><span lang=EN-US style='mso-ansi-language:
EN-US'><o:p></o:p></span></p>

<p class=MsoNormal style='margin-bottom:0cm;margin-bottom:.0001pt;line-height:
normal;text-autospace:none'><span lang=EN-US style='mso-ansi-language:EN-US'>&nbsp;<o:p></o:p></span></p>

<p class=MsoNormal style='margin-bottom:0cm;margin-bottom:.0001pt;line-height:
normal;text-autospace:none'><span lang=EN-US style='font-family:"Courier New";
mso-ansi-language:EN-US'>---------</span><span lang=EN-US style='mso-ansi-language:
EN-US'><o:p></o:p></span></p>

<p class=MsoNormal style='margin-bottom:0cm;margin-bottom:.0001pt;line-height:
normal;text-autospace:none'><span lang=EN-US style='font-family:"Courier New";
mso-ansi-language:EN-US'>2. Files:</span><span lang=EN-US style='mso-ansi-language:
EN-US'><o:p></o:p></span></p>

<p class=MsoNormal style='margin-bottom:0cm;margin-bottom:.0001pt;line-height:
normal;text-autospace:none'><span lang=EN-US style='font-family:"Courier New";
mso-ansi-language:EN-US'>---------</span><span lang=EN-US style='mso-ansi-language:
EN-US'><o:p></o:p></span></p>

<p class=MsoNormal style='margin-bottom:0cm;margin-bottom:.0001pt;line-height:
normal;text-autospace:none'><span lang=EN-US style='font-family:"Courier New";
mso-ansi-language:EN-US'>The following files are required to run one of the
simulations:</span><span lang=EN-US style='mso-ansi-language:EN-US'><o:p></o:p></span></p>

<p class=MsoNormal style='margin-bottom:0cm;margin-bottom:.0001pt;line-height:
normal;text-autospace:none'><span lang=EN-US style='font-family:"Courier New";
mso-ansi-language:EN-US'>&nbsp;</span><span lang=EN-US style='mso-ansi-language:
EN-US'><o:p></o:p></span></p>

<p class=MsoNormal style='margin-bottom:0cm;margin-bottom:.0001pt;line-height:
normal;text-autospace:none'><span lang=EN-US style='font-family:"Courier New";
mso-ansi-language:EN-US'>'Cav23.mod', which contains the Markov-type kinetic
model of Cav2.3 channels</span><span lang=EN-US style='mso-ansi-language:EN-US'><o:p></o:p></span></p>

<p class=MsoNormal style='margin-bottom:0cm;margin-bottom:.0001pt;line-height:
normal;text-autospace:none'><span lang=EN-US style='font-family:"Courier New";
mso-ansi-language:EN-US'>&nbsp;</span><span lang=EN-US style='mso-ansi-language:
EN-US'><o:p></o:p></span></p>

<p class=MsoNormal style='margin-bottom:0cm;margin-bottom:.0001pt;line-height:
normal;text-autospace:none'><span lang=EN-US style='font-family:"Courier New";
mso-ansi-language:EN-US'>'vclamp_pl.mod', which contains a voltage clamp model
with five levels that has been adopted from a previous model by <span
class=SpellE>Balbi</span> et al. (Accession: 230137) </span><span lang=EN-US
style='mso-ansi-language:EN-US'><o:p></o:p></span></p>

<p class=MsoNormal style='margin-bottom:0cm;margin-bottom:.0001pt;line-height:
normal;text-autospace:none'><span lang=EN-US style='font-family:"Courier New";
mso-ansi-language:EN-US'>&nbsp;</span><span lang=EN-US style='mso-ansi-language:
EN-US'><o:p></o:p></span></p>

<p class=MsoNormal style='margin-bottom:0cm;margin-bottom:.0001pt;line-height:
normal;text-autospace:none'><span lang=EN-US style='font-family:"Courier New";
mso-ansi-language:EN-US'>'IV <span class=SpellE>static.hoc</span>', 'IV <span
class=SpellE>dynamic.hoc</span>', '<span class=SpellE>IVlong</span> <span
class=SpellE>static.hoc</span>', '<span class=SpellE>IVlong</span> <span
class=SpellE>dynamic.hoc</span>', '<span class=SpellE>IIV.hoc</span>' or '<span
class=SpellE>PPI.hoc</span>', which contain the code for the different
simulations described in section 4 </span><span lang=EN-US style='mso-ansi-language:
EN-US'><o:p></o:p></span></p>

<p class=MsoNormal style='margin-bottom:0cm;margin-bottom:.0001pt;line-height:
normal;text-autospace:none'><span lang=EN-US style='font-family:"Courier New";
mso-ansi-language:EN-US'>&nbsp;</span><span lang=EN-US style='mso-ansi-language:
EN-US'><o:p></o:p></span></p>

<p class=MsoNormal style='margin-bottom:0cm;margin-bottom:.0001pt;line-height:
normal;text-autospace:none'><span lang=EN-US style='font-family:"Courier New";
mso-ansi-language:EN-US'>&nbsp;</span><span lang=EN-US style='mso-ansi-language:
EN-US'><o:p></o:p></span></p>

<p class=MsoNormal style='margin-bottom:0cm;margin-bottom:.0001pt;line-height:
normal;text-autospace:none'><span lang=EN-US style='font-family:"Courier New";
mso-ansi-language:EN-US'>&nbsp;&nbsp;</span><span lang=EN-US style='mso-ansi-language:
EN-US'><o:p></o:p></span></p>

<p class=MsoNormal style='margin-bottom:0cm;margin-bottom:.0001pt;line-height:
normal;text-autospace:none'><span lang=EN-US style='font-family:"Courier New";
mso-ansi-language:EN-US'>------------------------------------------------------------------</span><span
lang=EN-US style='mso-ansi-language:EN-US'><o:p></o:p></span></p>

<p class=MsoNormal style='margin-bottom:0cm;margin-bottom:.0001pt;line-height:
normal;text-autospace:none'><span lang=EN-US style='font-family:"Courier New";
mso-ansi-language:EN-US'>3. Compiling the mechanism (.mod) files and starting a
simulation:</span><span lang=EN-US style='mso-ansi-language:EN-US'><o:p></o:p></span></p>

<p class=MsoNormal style='margin-bottom:0cm;margin-bottom:.0001pt;line-height:
normal;text-autospace:none'><span lang=EN-US style='font-family:"Courier New";
mso-ansi-language:EN-US'>------------------------------------------------------------------</span><span
lang=EN-US style='mso-ansi-language:EN-US'><o:p></o:p></span></p>

<p class=MsoNormal style='margin-bottom:0cm;margin-bottom:.0001pt;line-height:
normal;text-autospace:none'><span lang=EN-US style='font-family:"Courier New";
mso-ansi-language:EN-US'>&nbsp;</span><span lang=EN-US style='mso-ansi-language:
EN-US'><o:p></o:p></span></p>

<p class=MsoNormal style='margin-bottom:0cm;margin-bottom:.0001pt;line-height:
normal;text-autospace:none'><span lang=EN-US style='font-family:"Courier New";
mso-ansi-language:EN-US'>Under <span class=SpellE>linux</span>:</span><span
lang=EN-US style='mso-ansi-language:EN-US'><o:p></o:p></span></p>

<p class=MsoNormal style='margin-bottom:0cm;margin-bottom:.0001pt;line-height:
normal;text-autospace:none'><span lang=EN-US style='font-family:"Courier New";
mso-ansi-language:EN-US'>------------</span><span lang=EN-US style='mso-ansi-language:
EN-US'><o:p></o:p></span></p>

<p class=MsoNormal style='margin-bottom:0cm;margin-bottom:.0001pt;line-height:
normal;text-autospace:none'><span lang=EN-US style='font-family:"Courier New";
mso-ansi-language:EN-US'>Compile the mod files using the command '<span
class=SpellE>nrnivmodl</span>'.</span><span lang=EN-US style='mso-ansi-language:
EN-US'><o:p></o:p></span></p>

<p class=MsoNormal style='margin-bottom:0cm;margin-bottom:.0001pt;line-height:
normal;text-autospace:none'><span lang=EN-US style='font-family:"Courier New";
mso-ansi-language:EN-US'>Use one of the following commands to start the
simulations:</span><span lang=EN-US style='mso-ansi-language:EN-US'><o:p></o:p></span></p>

<p class=MsoNormal style='margin-bottom:0cm;margin-bottom:.0001pt;line-height:
normal;text-autospace:none'><span lang=EN-US style='font-family:"Courier New";
mso-ansi-language:EN-US'>&nbsp;</span><span lang=EN-US style='mso-ansi-language:
EN-US'><o:p></o:p></span></p>

<p class=MsoNormal style='margin-bottom:0cm;margin-bottom:.0001pt;line-height:
normal;text-autospace:none'><span class=SpellE><span class=GramE><span
lang=EN-US style='font-family:"Courier New";mso-ansi-language:EN-US'>nrngui</span></span></span><span
lang=EN-US style='font-family:"Courier New";mso-ansi-language:EN-US'> IV <span
class=SpellE>static.hoc</span></span><span lang=EN-US style='mso-ansi-language:
EN-US'><o:p></o:p></span></p>

<p class=MsoNormal style='margin-bottom:0cm;margin-bottom:.0001pt;line-height:
normal;text-autospace:none'><span class=SpellE><span class=GramE><span
lang=EN-US style='font-family:"Courier New";mso-ansi-language:EN-US'>nrngui</span></span></span><span
lang=EN-US style='font-family:"Courier New";mso-ansi-language:EN-US'> IV <span
class=SpellE>dynamic.hoc</span></span><span lang=EN-US style='mso-ansi-language:
EN-US'><o:p></o:p></span></p>

<p class=MsoNormal style='margin-bottom:0cm;margin-bottom:.0001pt;line-height:
normal;text-autospace:none'><span class=SpellE><span class=GramE><span
lang=EN-US style='font-family:"Courier New";mso-ansi-language:EN-US'>nrngui</span></span></span><span
lang=EN-US style='font-family:"Courier New";mso-ansi-language:EN-US'> <span
class=SpellE>IVlong</span> <span class=SpellE>static.hoc</span></span><span
lang=EN-US style='mso-ansi-language:EN-US'><o:p></o:p></span></p>

<p class=MsoNormal style='margin-bottom:0cm;margin-bottom:.0001pt;line-height:
normal;text-autospace:none'><span class=SpellE><span class=GramE><span
lang=EN-US style='font-family:"Courier New";mso-ansi-language:EN-US'>nrngui</span></span></span><span
lang=EN-US style='font-family:"Courier New";mso-ansi-language:EN-US'> <span
class=SpellE>IVlong</span> <span class=SpellE>dynamic.hoc</span></span><span
lang=EN-US style='mso-ansi-language:EN-US'><o:p></o:p></span></p>

<p class=MsoNormal style='margin-bottom:0cm;margin-bottom:.0001pt;line-height:
normal;text-autospace:none'><span class=SpellE><span class=GramE><span
lang=EN-US style='font-family:"Courier New";mso-ansi-language:EN-US'>nrngui</span></span></span><span
lang=EN-US style='font-family:"Courier New";mso-ansi-language:EN-US'> <span
class=SpellE>IIV.hoc</span></span><span lang=EN-US style='mso-ansi-language:
EN-US'><o:p></o:p></span></p>

<p class=MsoNormal style='margin-bottom:0cm;margin-bottom:.0001pt;line-height:
normal;text-autospace:none'><span class=SpellE><span class=GramE><span
lang=EN-US style='font-family:"Courier New";mso-ansi-language:EN-US'>nrngui</span></span></span><span
lang=EN-US style='font-family:"Courier New";mso-ansi-language:EN-US'> <span
class=SpellE>PPI.hoc</span></span><span lang=EN-US style='mso-ansi-language:
EN-US'><o:p></o:p></span></p>

<p class=MsoNormal style='margin-bottom:0cm;margin-bottom:.0001pt;line-height:
normal;text-autospace:none'><span lang=EN-US style='font-family:"Courier New";
mso-ansi-language:EN-US'>&nbsp;</span><span lang=EN-US style='mso-ansi-language:
EN-US'><o:p></o:p></span></p>

<p class=MsoNormal style='margin-bottom:0cm;margin-bottom:.0001pt;line-height:
normal;text-autospace:none'><span lang=EN-US style='font-family:"Courier New";
mso-ansi-language:EN-US'>&nbsp;</span><span lang=EN-US style='mso-ansi-language:
EN-US'><o:p></o:p></span></p>

<p class=MsoNormal style='margin-bottom:0cm;margin-bottom:.0001pt;line-height:
normal;text-autospace:none'><span lang=EN-US style='font-family:"Courier New";
mso-ansi-language:EN-US'>Under Windows:</span><span lang=EN-US
style='mso-ansi-language:EN-US'><o:p></o:p></span></p>

<p class=MsoNormal style='margin-bottom:0cm;margin-bottom:.0001pt;line-height:
normal;text-autospace:none'><span lang=EN-US style='font-family:"Courier New";
mso-ansi-language:EN-US'>--------------</span><span lang=EN-US
style='mso-ansi-language:EN-US'><o:p></o:p></span></p>

<p class=MsoNormal style='margin-bottom:0cm;margin-bottom:.0001pt;line-height:
normal;text-autospace:none'><span lang=EN-US style='font-family:"Courier New";
mso-ansi-language:EN-US'>Run '<span class=SpellE>mknrndll</span>' to compile
the mod files.</span><span lang=EN-US style='mso-ansi-language:EN-US'><o:p></o:p></span></p>

<p class=MsoNormal style='margin-bottom:0cm;margin-bottom:.0001pt;line-height:
normal;text-autospace:none'><span lang=EN-US style='font-family:"Courier New";
mso-ansi-language:EN-US'>Double click on one of the hoc files to start the
simulations.</span><span lang=EN-US style='mso-ansi-language:EN-US'><o:p></o:p></span></p>

<p class=MsoNormal style='margin-bottom:0cm;margin-bottom:.0001pt;line-height:
normal;text-autospace:none'><span lang=EN-US style='font-family:"Courier New";
mso-ansi-language:EN-US'>&nbsp;</span><span lang=EN-US style='mso-ansi-language:
EN-US'><o:p></o:p></span></p>

<p class=MsoNormal style='margin-bottom:0cm;margin-bottom:.0001pt;line-height:
normal;text-autospace:none'><span lang=EN-US style='font-family:"Courier New";
mso-ansi-language:EN-US'>&nbsp;</span><span lang=EN-US style='mso-ansi-language:
EN-US'><o:p></o:p></span></p>

<p class=MsoNormal style='margin-bottom:0cm;margin-bottom:.0001pt;line-height:
normal;text-autospace:none'><span lang=EN-US style='font-family:"Courier New";
mso-ansi-language:EN-US'>Under MAC OS X:</span><span lang=EN-US
style='mso-ansi-language:EN-US'><o:p></o:p></span></p>

<p class=MsoNormal style='margin-bottom:0cm;margin-bottom:.0001pt;line-height:
normal;text-autospace:none'><span lang=EN-US style='font-family:"Courier New";
mso-ansi-language:EN-US'>---------------</span><span lang=EN-US
style='mso-ansi-language:EN-US'><o:p></o:p></span></p>

<p class=MsoNormal style='margin-bottom:0cm;margin-bottom:.0001pt;line-height:
normal;text-autospace:none'><span lang=EN-US style='font-family:"Courier New";
mso-ansi-language:EN-US'>Drag the model folder onto the <span class=SpellE>mknrndll</span>
icon to compile the mod files.</span><span lang=EN-US style='mso-ansi-language:
EN-US'><o:p></o:p></span></p>

<p class=MsoNormal style='margin-bottom:0cm;margin-bottom:.0001pt;line-height:
normal;text-autospace:none'><span lang=EN-US style='font-family:"Courier New";
mso-ansi-language:EN-US'>Drag one of the hoc files onto the <span class=SpellE>nrngui</span>
icon to start the simulations.</span><span lang=EN-US style='mso-ansi-language:
EN-US'><o:p></o:p></span></p>

<p class=MsoNormal style='margin-bottom:0cm;margin-bottom:.0001pt;line-height:
normal;text-autospace:none'><span lang=EN-US style='font-family:"Courier New";
mso-ansi-language:EN-US'>&nbsp;</span><span lang=EN-US style='mso-ansi-language:
EN-US'><o:p></o:p></span></p>

<p class=MsoNormal style='margin-bottom:0cm;margin-bottom:.0001pt;line-height:
normal;text-autospace:none'><span lang=EN-US style='font-family:"Courier New";
mso-ansi-language:EN-US'>&nbsp;</span><span lang=EN-US style='mso-ansi-language:
EN-US'><o:p></o:p></span></p>

<p class=MsoNormal style='margin-bottom:0cm;margin-bottom:.0001pt;line-height:
normal;text-autospace:none'><span lang=EN-US style='font-family:"Courier New";
mso-ansi-language:EN-US'>More information on running NEURON models can be found
at</span><span lang=EN-US style='mso-ansi-language:EN-US'><o:p></o:p></span></p>

<p class=MsoNormal style='margin-bottom:0cm;margin-bottom:.0001pt;line-height:
normal;text-autospace:none'><span style='font-family:"Courier New"'><a
href="https://senselab.med.yale.edu/ModelDB/NEURON_DwnldGuide.htm"><span
lang=EN-US style='color:windowtext;mso-ansi-language:EN-US;text-decoration:
none;text-underline:none'>https://senselab.med.yale.edu/ModelDB/NEURON_DwnldGuide.htm</span></a></span><span
lang=EN-US style='mso-ansi-language:EN-US'><o:p></o:p></span></p>

<p class=MsoNormal style='margin-bottom:0cm;margin-bottom:.0001pt;line-height:
normal;text-autospace:none'><span lang=EN-US style='font-family:"Courier New";
mso-ansi-language:EN-US'>&nbsp;</span><span lang=EN-US style='mso-ansi-language:
EN-US'><o:p></o:p></span></p>

<p class=MsoNormal style='margin-bottom:0cm;margin-bottom:.0001pt;line-height:
normal;text-autospace:none'><span lang=EN-US style='mso-ansi-language:EN-US'>&nbsp;<o:p></o:p></span></p>

<p class=MsoNormal style='margin-bottom:0cm;margin-bottom:.0001pt;line-height:
normal;text-autospace:none'><span lang=EN-US style='font-family:"Courier New";
mso-ansi-language:EN-US'>&nbsp;</span><span lang=EN-US style='mso-ansi-language:
EN-US'><o:p></o:p></span></p>

<p class=MsoNormal style='margin-bottom:0cm;margin-bottom:.0001pt;line-height:
normal;text-autospace:none'><span lang=EN-US style='font-family:"Courier New";
mso-ansi-language:EN-US'>----------------------</span><span lang=EN-US
style='mso-ansi-language:EN-US'><o:p></o:p></span></p>

<p class=MsoNormal style='margin-bottom:0cm;margin-bottom:.0001pt;line-height:
normal;text-autospace:none'><span lang=EN-US style='font-family:"Courier New";
mso-ansi-language:EN-US'>4. Simulation control:</span><span lang=EN-US
style='mso-ansi-language:EN-US'><o:p></o:p></span></p>

<p class=MsoNormal style='margin-bottom:0cm;margin-bottom:.0001pt;line-height:
normal;text-autospace:none'><span lang=EN-US style='font-family:"Courier New";
mso-ansi-language:EN-US'>----------------------</span><span lang=EN-US
style='mso-ansi-language:EN-US'><o:p></o:p></span></p>

<p class=MsoNormal style='margin-bottom:0cm;margin-bottom:.0001pt;line-height:
normal;text-autospace:none'><span lang=EN-US style='font-family:"Courier New";
mso-ansi-language:EN-US'>When one of the hoc files is started, several panels
for simulation control will appear. The <i>Clamp Control </i>panel (middle)
contains the start button for running simulations and several clamp parameters,
which can be changed by the user to modify the default voltage protocol. The <span
class=SpellE><i>CaR</i></span><i> Control </i>panel (bottom) provides control
over the number of channels per cm<sup>2</sup>, the single channel permeability
and the free Zn<sup>2+</sup> concentration (in <span class=SpellE>mM</span>).
The simulation speed can be adjusted by reducing or increasing the value of <span
class=SpellE><span class=GramE>dt</span></span> in the <i>Run Control </i>panel
(top). </span><span lang=EN-US style='mso-ansi-language:EN-US'><o:p></o:p></span></p>

<p class=MsoNormal style='margin-bottom:0cm;margin-bottom:.0001pt;line-height:
normal;text-autospace:none'><span lang=EN-US style='font-family:"Courier New";
mso-ansi-language:EN-US'>&nbsp;</span><span lang=EN-US style='mso-ansi-language:
EN-US'><o:p></o:p></span></p>

<p class=MsoNormal style='margin-bottom:0cm;margin-bottom:.0001pt;line-height:
normal;text-autospace:none'><span style='font-family:"Courier New";mso-no-proof:
yes'><img border=0 width=757 height=627 id="_x0000_i1025"
src="readme-Dateien/image002.jpg"
alt="Beschreibung: Beschreibung: Beschreibung: Beschreibung: Beschreibung: C:\Users\Felix\Dropbox\5. MANUSCRIPTS\Eigene\Zn Effects and Model Neu\Model (Site 1+2)\New folder\Final_Revised\Cav23\readme-Dateien\image002.jpg"></span></p>

<p class=MsoNormal style='margin-bottom:0cm;margin-bottom:.0001pt;line-height:
normal;text-autospace:none'><span lang=EN-US style='font-family:"Courier New";
mso-ansi-language:EN-US'>&nbsp;</span><span lang=EN-US style='mso-ansi-language:
EN-US'><o:p></o:p></span></p>

<p class=MsoNormal style='margin-bottom:0cm;margin-bottom:.0001pt;line-height:
normal;text-autospace:none'><span lang=EN-US style='font-family:"Courier New";
mso-ansi-language:EN-US'>IV <span class=SpellE>static.hoc</span>:</span><span
lang=EN-US style='mso-ansi-language:EN-US'><o:p></o:p></span></p>

<p class=MsoNormal style='margin-bottom:0cm;margin-bottom:.0001pt;line-height:
normal;text-autospace:none'><span lang=EN-US style='font-family:"Courier New";
mso-ansi-language:EN-US'>-------------- </span><span lang=EN-US
style='mso-ansi-language:EN-US'><o:p></o:p></span></p>

<p class=MsoNormal style='margin-bottom:0cm;margin-bottom:.0001pt;line-height:
normal;text-autospace:none'><span lang=EN-US style='font-family:"Courier New";
mso-ansi-language:EN-US'>With the default clamp parameters, a click on the
start button generates a family of current traces (bottom window) evoked with
the same voltage protocol (top window) as that used in Fig. 15C, 16A and 17A
(left panel) of the paper. </span><span lang=EN-US style='mso-ansi-language:
EN-US'><o:p></o:p></span></p>

<p class=MsoNormal style='margin-bottom:0cm;margin-bottom:.0001pt;line-height:
normal;text-autospace:none'><span lang=EN-US style='font-family:"Courier New";
mso-ansi-language:EN-US'>&nbsp;</span><span lang=EN-US style='mso-ansi-language:
EN-US'><o:p></o:p></span></p>

<p class=MsoNormal style='margin-bottom:0cm;margin-bottom:.0001pt;line-height:
normal;text-autospace:none'><span lang=EN-US style='mso-ansi-language:EN-US'>&nbsp;<o:p></o:p></span></p>

<p class=MsoNormal style='margin-bottom:0cm;margin-bottom:.0001pt;line-height:
normal;text-autospace:none'><span lang=EN-US style='font-family:"Courier New";
mso-ansi-language:EN-US'>IV <span class=SpellE>dynamic.hoc</span>: </span><span
lang=EN-US style='mso-ansi-language:EN-US'><o:p></o:p></span></p>

<p class=MsoNormal style='margin-bottom:0cm;margin-bottom:.0001pt;line-height:
normal;text-autospace:none'><span lang=EN-US style='font-family:"Courier New";
mso-ansi-language:EN-US'>---------------</span><span lang=EN-US
style='mso-ansi-language:EN-US'><o:p></o:p></span></p>

<p class=MsoNormal style='margin-bottom:0cm;margin-bottom:.0001pt;line-height:
normal;text-autospace:none'><span lang=EN-US style='font-family:"Courier New";
mso-ansi-language:EN-US'>With the default clamp parameters, a click on the
start button runs a dynamic simulation with the same voltage protocol as above
but a clamping increment of 1 mV and plots the peak current-voltage
relationship. </span><span lang=EN-US style='mso-ansi-language:EN-US'><o:p></o:p></span></p>

<p class=MsoNormal style='margin-bottom:0cm;margin-bottom:.0001pt;line-height:
normal;text-autospace:none'><span lang=EN-US style='font-family:"Courier New";
mso-ansi-language:EN-US'>&nbsp;</span><span lang=EN-US style='mso-ansi-language:
EN-US'><o:p></o:p></span></p>

<p class=MsoNormal style='margin-bottom:0cm;margin-bottom:.0001pt;line-height:
normal;text-autospace:none'><span lang=EN-US style='font-family:"Courier New";
mso-ansi-language:EN-US'>&nbsp;</span><span lang=EN-US style='mso-ansi-language:
EN-US'><o:p></o:p></span></p>

<p class=MsoNormal style='margin-bottom:0cm;margin-bottom:.0001pt;line-height:
normal;text-autospace:none'><span class=SpellE><span lang=EN-US
style='font-family:"Courier New";mso-ansi-language:EN-US'>IVlong</span></span><span
lang=EN-US style='font-family:"Courier New";mso-ansi-language:EN-US'> <span
class=SpellE>static.hoc</span>:</span><span lang=EN-US style='mso-ansi-language:
EN-US'><o:p></o:p></span></p>

<p class=MsoNormal style='margin-bottom:0cm;margin-bottom:.0001pt;line-height:
normal;text-autospace:none'><span lang=EN-US style='font-family:"Courier New";
mso-ansi-language:EN-US'>------------------&nbsp; </span><span lang=EN-US
style='mso-ansi-language:EN-US'><o:p></o:p></span></p>

<p class=MsoNormal style='margin-bottom:0cm;margin-bottom:.0001pt;line-height:
normal;text-autospace:none'><span lang=EN-US style='font-family:"Courier New";
mso-ansi-language:EN-US'>With the default clamp parameters, a click on the start
button generates a family of current traces (bottom window) evoked with the
same voltage protocol (top window) as that used in Fig. 15F and 17A (right
panel) of the paper. </span><span lang=EN-US style='mso-ansi-language:EN-US'><o:p></o:p></span></p>

<p class=MsoNormal style='margin-bottom:0cm;margin-bottom:.0001pt;line-height:
normal;text-autospace:none'><span lang=EN-US style='font-family:"Courier New";
mso-ansi-language:EN-US'>&nbsp;</span><span lang=EN-US style='mso-ansi-language:
EN-US'><o:p></o:p></span></p>

<p class=MsoNormal style='margin-bottom:0cm;margin-bottom:.0001pt;line-height:
normal;text-autospace:none'><span lang=EN-US style='mso-ansi-language:EN-US'>&nbsp;<o:p></o:p></span></p>

<p class=MsoNormal style='margin-bottom:0cm;margin-bottom:.0001pt;line-height:
normal;text-autospace:none'><span class=SpellE><span lang=EN-US
style='font-family:"Courier New";mso-ansi-language:EN-US'>IVlong</span></span><span
lang=EN-US style='font-family:"Courier New";mso-ansi-language:EN-US'> <span
class=SpellE>dynamic.hoc</span>:</span><span lang=EN-US style='mso-ansi-language:
EN-US'><o:p></o:p></span></p>

<p class=MsoNormal style='margin-bottom:0cm;margin-bottom:.0001pt;line-height:
normal;text-autospace:none'><span lang=EN-US style='font-family:"Courier New";
mso-ansi-language:EN-US'>------------------- </span><span lang=EN-US
style='mso-ansi-language:EN-US'><o:p></o:p></span></p>

<p class=MsoNormal style='margin-bottom:0cm;margin-bottom:.0001pt;line-height:
normal;text-autospace:none'><span lang=EN-US style='font-family:"Courier New";
mso-ansi-language:EN-US'>With the default clamp parameters, a click on the
start button runs a dynamic simulation with the same voltage protocol as above
but a clamping increment of 1 mV and plots the peak current-voltage
relationship. </span><span lang=EN-US style='mso-ansi-language:EN-US'><o:p></o:p></span></p>

<p class=MsoNormal style='margin-bottom:0cm;margin-bottom:.0001pt;line-height:
normal;text-autospace:none'><span lang=EN-US style='font-family:"Courier New";
mso-ansi-language:EN-US'>&nbsp;</span><span lang=EN-US style='mso-ansi-language:
EN-US'><o:p></o:p></span></p>

<p class=MsoNormal style='margin-bottom:0cm;margin-bottom:.0001pt;line-height:
normal;text-autospace:none'><span lang=EN-US style='font-family:"Courier New";
mso-ansi-language:EN-US'>&nbsp;</span><span lang=EN-US style='mso-ansi-language:
EN-US'><o:p></o:p></span></p>

<p class=MsoNormal style='margin-bottom:0cm;margin-bottom:.0001pt;line-height:
normal;text-autospace:none'><span class=SpellE><span lang=EN-US
style='font-family:"Courier New";mso-ansi-language:EN-US'>IIV.hoc</span></span><span
lang=EN-US style='font-family:"Courier New";mso-ansi-language:EN-US'>: </span><span
lang=EN-US style='mso-ansi-language:EN-US'><o:p></o:p></span></p>

<p class=MsoNormal style='margin-bottom:0cm;margin-bottom:.0001pt;line-height:
normal;text-autospace:none'><span lang=EN-US style='font-family:"Courier New";
mso-ansi-language:EN-US'>--------</span><span lang=EN-US style='mso-ansi-language:
EN-US'><o:p></o:p></span></p>

<p class=MsoNormal style='margin-bottom:0cm;margin-bottom:.0001pt;line-height:
normal;text-autospace:none'><span lang=EN-US style='font-family:"Courier New";
mso-ansi-language:EN-US'>With the default clamp parameters, a click on the
start button generates a family of current traces (bottom window) evoked with
the same voltage protocol (top window) as that used in Fig. 15D, 16C and 17B of
the paper. </span><span lang=EN-US style='mso-ansi-language:EN-US'><o:p></o:p></span></p>

<p class=MsoNormal style='margin-bottom:0cm;margin-bottom:.0001pt;line-height:
normal;text-autospace:none'><span lang=EN-US style='font-family:"Courier New";
mso-ansi-language:EN-US'>&nbsp;</span><span lang=EN-US style='mso-ansi-language:
EN-US'><o:p></o:p></span></p>

<p class=MsoNormal style='margin-bottom:0cm;margin-bottom:.0001pt;line-height:
normal;text-autospace:none'><span lang=EN-US style='font-family:"Courier New";
mso-ansi-language:EN-US'>&nbsp;</span><span lang=EN-US style='mso-ansi-language:
EN-US'><o:p></o:p></span></p>

<p class=MsoNormal style='margin-bottom:0cm;margin-bottom:.0001pt;line-height:
normal;text-autospace:none'><span class=SpellE><span lang=EN-US
style='font-family:"Courier New";mso-ansi-language:EN-US'>PPI.hoc</span></span><span
lang=EN-US style='font-family:"Courier New";mso-ansi-language:EN-US'>: </span><span
lang=EN-US style='mso-ansi-language:EN-US'><o:p></o:p></span></p>

<p class=MsoNormal style='margin-bottom:0cm;margin-bottom:.0001pt;line-height:
normal;text-autospace:none'><span lang=EN-US style='font-family:"Courier New";
mso-ansi-language:EN-US'>--------</span><span lang=EN-US style='mso-ansi-language:
EN-US'><o:p></o:p></span></p>

<p class=MsoNormal style='margin-bottom:0cm;margin-bottom:.0001pt;line-height:
normal;text-autospace:none'><span lang=EN-US style='font-family:"Courier New";
mso-ansi-language:EN-US'>With the default clamp parameters, a click on the
start button generates a family of current traces (bottom window) evoked with
the same voltage protocol (top window) as that used in Fig. 15E and 16B of the
paper and plots the normalized pre-pulse inactivation relationship. The
simulation speed can be increased by deselecting the Display Button at the
bottom of the Clamp Control panel, which switches off display of the current
traces during the simulation. </span><span lang=EN-US style='mso-ansi-language:
EN-US'><o:p></o:p></span></p>

<p class=MsoNormal style='margin-bottom:0cm;margin-bottom:.0001pt;line-height:
normal;text-autospace:none'><span lang=EN-US style='font-family:"Courier New";
mso-ansi-language:EN-US'>&nbsp;</span><span lang=EN-US style='mso-ansi-language:
EN-US'><o:p></o:p></span></p>

<p class=MsoNormal style='margin-bottom:0cm;margin-bottom:.0001pt;line-height:
normal;text-autospace:none'><span lang=EN-US style='font-family:"Courier New";
mso-ansi-language:EN-US'>&nbsp;&nbsp;&nbsp;&nbsp; </span><span lang=EN-US
style='mso-ansi-language:EN-US'><o:p></o:p></span></p>

<p class=MsoNormal><span lang=EN-US style='mso-ansi-language:EN-US'>&nbsp;<o:p></o:p></span></p>

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A Markov model of human Cav2.3 channels and their modulation by Zn2+ (Neumaier et al 2020)

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