[Cusom26] From Dr. Petrovic - A board question about CFTR gating

[CUSOM Medical Education]

Please see below for a message from Dr. Petrovic-


Hello everyone,

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?

The reason I do not talk about ATP and CFTR gating is exactly that: it is confusing and clinical relevance is not the ATP-binding process, but the cAMP-dependent phosphorylation, which is targeted by bacterial toxins. Namely, the cAMP-driven phosphorylation of CFTR is a prerequisite for CFTR gating by ATP.

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, CFTR is the only 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, CFTR mediates a passive diffusion of chloride down the chloride electrochemical gradient. 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. This phenomenon, unique to CFTR, likely reflects the evolutionary relationship of CFTR: an ABC transporter turned an ion channel.

Please let me know if this clarifies the issue.

Too bad this was my last lecture for your class. I will miss your insightful questions/points.

All best,
Snezana

P.S.
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):
Cold Spring Harb Perspect Med. 2013 Jan; 3(1): a009498. doi: 10.1101/cshperspect.a009498; The CFTR Ion Channel: Gating, Regulation, and Anion Permeation; Tzyh-Chang Hwang1 and Kevin L. Kirk2

Structure, Gating, and Regulation of the CFTR Anion Channel; László Csanády,Paola Vergani, andDavid C. Gadsby;  2018 https://doi.org/10.1152/physrev.00007.2018

The question
[A screenshot of a computer  Description automatically generated]


Snežana Petrović, MD, PhD, MHPE, FASN | Associate Professor of Physiology
School of Osteopathic Medicine | Campbell University
4350 US 421 South | Lillington, NC  27546
Levine Hall | 910-893-1751 | medicine.campbell.edu<http://medicine.campbell.edu/>
spetrovic at campbell.edu<mailto:spetrovic at campbell.edu>

[cid:image001.png at 01DA5918.D9135160]<http://medicine.campbell.edu/>

CONFIDENTIALITY NOTICE: This e-mail, including any attachments, is intended for the sole use of the addressee(s) and may contain legally privileged and/or confidential information.  If you are not the intended recipient, you are hereby notified that any use, dissemination, copying or retention of this e-mail or the information contained herein is strictly prohibited.  If you have received this e-mail in error, please immediately notify the sender by telephone or reply by e-mail, and permanently delete this e-mail from your computer system.  There is no intent on the part of the sender to waive any privilege, including the attorney-client privilege, that may attach to this communication.  Thank you. IF YOU HAVE RECEIVED THIS IN ERROR, PLEASE CALL ME IMMEDIATELY AT 910-893-1751.


-------------- next part --------------
An HTML attachment was scrubbed...
URL: <https://list.campbell.edu/pipermail/cusom26/attachments/20240206/81968290/attachment.htm>
-------------- next part --------------
A non-text attachment was scrubbed...
Name: image001.png
Type: image/png
Size: 7343 bytes
Desc: image001.png
URL: <https://list.campbell.edu/pipermail/cusom26/attachments/20240206/81968290/attachment.png>
-------------- next part --------------
A non-text attachment was scrubbed...
Name: image002.png
Type: image/png
Size: 300222 bytes
Desc: image002.png
URL: <https://list.campbell.edu/pipermail/cusom26/attachments/20240206/81968290/attachment-0001.png>