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<p class="MsoNormal"><span style="font-size:11.0pt;font-family:"Calibri",sans-serif;color:windowtext">Please see below for a message from Dr. Petrovic-
<o:p></o:p></span></p>
<p class="MsoNormal"><span style="font-size:11.0pt;font-family:"Calibri",sans-serif;color:windowtext"><o:p> </o:p></span></p>
<p class="MsoNormal"><span style="font-size:14.0pt;font-family:"Candara",sans-serif;color:#1F1F1F;background:white"><o:p> </o:p></span></p>
<p class="MsoNormal"><span style="font-size:14.0pt;font-family:"Candara",sans-serif;color:#1F1F1F;background:white">Hello everyone,<o:p></o:p></span></p>
<p class="MsoNormal"><span style="font-size:14.0pt;font-family:"Candara",sans-serif;color:#1F1F1F;background:white"><o:p> </o:p></span></p>
<p class="MsoNormal"><span style="font-size:14.0pt;font-family:"Candara",sans-serif;color:#1F1F1F;background:white">William came across a broad prep question (scroll below) asking about CFTR gating and he brought up an interesting point: if CFTR is an ATP-gated
ion channel, does that fact classify it as a primary active transporter or is it still a passive ion transporter/channel?
<o:p></o:p></span></p>
<p class="MsoNormal"><span style="font-size:14.0pt;font-family:"Candara",sans-serif;color:#1F1F1F;background:white"><o:p> </o:p></span></p>
<p class="MsoNormal"><span style="font-size:14.0pt;font-family:"Candara",sans-serif;color:#1F1F1F;background:white">The reason I do not talk about ATP and CFTR gating is exactly that: it is confusing and
<b>clinical relevance is not the ATP-binding process, but the cAMP-dependent </b>
</span><b><span style="font-size:15.0pt;font-family:"Candara",sans-serif;color:#212121;background:white">phosphorylation, which is targeted by bacterial toxins.</span></b><span style="font-size:15.0pt;font-family:"Candara",sans-serif;color:#212121;background:white">
Namely, the cAMP-driven phosphorylation of CFTR is <u>a</u> <u>prerequisite</u> for CFTR gating by ATP</span>.
<span style="font-size:14.0pt;font-family:"Candara",sans-serif;color:#1F1F1F;background:white">
<o:p></o:p></span></p>
<p class="MsoNormal"><span style="font-size:14.0pt;font-family:"Candara",sans-serif;color:#1F1F1F;background:white"><o:p> </o:p></span></p>
<p class="MsoNormal"><span style="font-size:14.0pt;font-family:"Candara",sans-serif;color:#1F1F1F;background:white">Opening and closing (gating) of the CFTR anion pore is largely regulated by two main processes: first (!), cAMP–dependent phosphorylation of
the regulatory domain, and second, the gating of a phosphorylated CFTR channel is driven by binding of ATP. In fact,
</span><span style="font-size:15.0pt;font-family:"Candara",sans-serif;color:#212121;background:white">CFTR is
<u>the only</u> ligand-gated channel that consumes its ligand (ATP) during the gating cycle—a consequence of its enzymatic activity as an ABC transporter. CFTR belongs to a family of transporters known as ATP-binding cassette (ABC transporters), most of which
are primary active transporters, the “pumps” that transport against the gradient using the energy from ATP hydrolysis. Not CFTR. Once open, CFTR still needs a favorable chloride gradient brought up by the activity of the basolateral NKCC1, as I explained.
So, <b>CFTR mediates a passive diffusion of chloride down the chloride electrochemical gradient.</b> What does CFTR use the ATP energy for then? Curiously enough, a good deal of it for the channel closure, but that does not make it a primary active transporter</span><span style="font-size:16.0pt;font-family:"Candara",sans-serif;color:windowtext;background:white">.
</span><span style="font-size:14.0pt;font-family:"Candara",sans-serif;color:windowtext">This phenomenon, unique to CFTR, likely reflects the evolutionary relationship of CFTR: an ABC transporter turned an ion channel.</span><span style="font-size:11.0pt;font-family:"Calibri",sans-serif;color:windowtext"><o:p></o:p></span></p>
<p class="MsoNormal"><span style="font-size:14.0pt;font-family:"Candara",sans-serif;color:#1F1F1F;background:white"><o:p> </o:p></span></p>
<p class="MsoNormal"><span style="font-size:14.0pt;font-family:"Candara",sans-serif;color:#1F1F1F;background:white">Please let me know if this clarifies the issue.<o:p></o:p></span></p>
<p class="MsoNormal"><span style="font-size:14.0pt;font-family:"Candara",sans-serif;color:#1F1F1F;background:white"><o:p> </o:p></span></p>
<p class="MsoNormal"><span style="font-size:14.0pt;font-family:"Candara",sans-serif;color:#1F1F1F;background:white">Too bad this was my last lecture for your class. I will miss your insightful questions/points.
<o:p></o:p></span></p>
<p class="MsoNormal"><span style="font-size:14.0pt;font-family:"Candara",sans-serif;color:#1F1F1F;background:white;mso-ligatures:none"><o:p> </o:p></span></p>
<p class="MsoNormal"><span style="font-size:14.0pt;font-family:"Candara",sans-serif;color:#1F1F1F;background:white;mso-ligatures:none">All best,<o:p></o:p></span></p>
<p class="MsoNormal"><span style="font-size:14.0pt;font-family:"Candara",sans-serif;color:#1F1F1F;background:white;mso-ligatures:none">Snezana</span><span style="font-size:14.0pt;font-family:"Candara",sans-serif;color:#2F5496"><o:p></o:p></span></p>
<p class="MsoNormal"><span style="font-size:14.0pt;font-family:"Candara",sans-serif;color:#1F1F1F;background:white"><o:p> </o:p></span></p>
<p class="MsoNormal"><span style="font-size:14.0pt;font-family:"Candara",sans-serif;color:#1F1F1F;background:white">P.S.<o:p></o:p></span></p>
<p class="MsoNormal"><span style="font-size:14.0pt;font-family:"Candara",sans-serif;color:#1F1F1F;background:white">For the curious types among you, with enough time to “waste” on nuances of CFTR gating extra info can be found in these references (that eventually
will help us with the design of CFTR-modulating drugs): <o:p></o:p></span></p>
<p class="MsoNormal"><span style="font-size:14.0pt;font-family:"Candara",sans-serif;color:#1F1F1F;background:white">Cold Spring Harb Perspect Med. 2013 Jan; 3(1): a009498. doi: 10.1101/cshperspect.a009498;
<i>The CFTR Ion Channel: Gating, Regulation, and Anion Permeation</i>; Tzyh-Chang Hwang1 and Kevin L. Kirk2<o:p></o:p></span></p>
<p class="MsoNormal"><span style="font-size:15.0pt;font-family:"Candara",sans-serif;color:#212121;background:white"><o:p> </o:p></span></p>
<p class="MsoNormal"><i><span style="font-size:15.0pt;font-family:"Candara",sans-serif;color:#212121;background:white">Structure, Gating, and Regulation of the CFTR Anion Channel</span></i><span style="font-size:15.0pt;font-family:"Candara",sans-serif;color:#212121;background:white">;
László Csanády,Paola Vergani, andDavid C. Gadsby; 2018 <a href="https://doi.org/10.1152/physrev.00007.2018">
https://doi.org/10.1152/physrev.00007.2018</a><o:p></o:p></span></p>
<p class="MsoNormal"><span style="font-size:14.0pt;font-family:"Candara",sans-serif;color:#2F5496"><o:p> </o:p></span></p>
<p class="MsoNormal"><span style="font-size:15.0pt;font-family:"Candara",sans-serif;color:#212121;background:white">The question<o:p></o:p></span></p>
<p class="MsoNormal"><img border="0" width="463" height="382" style="width:4.8263in;height:3.9791in" id="Picture_x0020_2" src="cid:image002.png@01DA5918.F0F5AAD0" alt="A screenshot of a computer
Description automatically generated"><span style="font-size:11.0pt;font-family:"Calibri",sans-serif;color:windowtext"><o:p></o:p></span></p>
<p class="MsoNormal"><span style="font-size:14.0pt;font-family:"Candara",sans-serif;color:#2F5496"><o:p> </o:p></span></p>
<p class="MsoNormal"><span style="font-size:14.0pt;font-family:"Candara",sans-serif;color:#2F5496"><o:p> </o:p></span></p>
<p class="MsoNormal" style="text-autospace:none"><b><span style="font-size:10.0pt;font-family:"Candara",sans-serif;color:#767171;mso-ligatures:none">Sneľana Petrović, MD, PhD, MHPE, FASN</span></b><span style="font-size:10.0pt;font-family:"Candara",sans-serif;color:#767171;mso-ligatures:none">
| Associate Professor of Physiology<o:p></o:p></span></p>
<p class="MsoNormal" style="text-autospace:none"><span style="font-size:10.0pt;font-family:"Candara",sans-serif;color:#767171;mso-ligatures:none">School of Osteopathic Medicine | Campbell University<o:p></o:p></span></p>
<p class="MsoNormal" style="text-autospace:none"><span style="font-size:10.0pt;font-family:"Candara",sans-serif;color:#767171;mso-ligatures:none">4350 US 421 South | Lillington, NC 27546<o:p></o:p></span></p>
<p class="MsoNormal" style="text-autospace:none"><span style="font-size:10.0pt;font-family:"Candara",sans-serif;color:#767171;mso-ligatures:none">Levine Hall | 910-893-1751 | </span><span style="font-size:11.0pt;font-family:"Calibri",sans-serif;color:#2F5496;mso-ligatures:none"><a href="http://medicine.campbell.edu/"><span style="font-size:10.0pt;font-family:"Candara",sans-serif;color:#767171">medicine.campbell.edu</span></a></span><span style="font-size:10.0pt;font-family:"Candara",sans-serif;color:#767171;mso-ligatures:none"><o:p></o:p></span></p>
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