PhD Scientific Days 2023

Molecular Sciences - Posters K

Exploring the Impact of the Cystic Fibrosis Causing Mutations ΔF508 and G551D on the CFTR – PKA Interaction

Előadó neve

Simon, Marton

Neptun code

V5SDTB

Előadó munkahelye

Semmelweis University

Előadó telefonszáma

+36304224806

Előadó e-mail címe

simonmarton1@gmail.com

Az előadás címe

Exploring the Impact of the Cystic Fibrosis Causing Mutations ΔF508 and G551D on the CFTR – PKA Interaction

Szerző(k) neve és munkahelye

Márton A Simon, László Csanády
Department of Biochemistry, Semmelweis University

Bemutatás módja

Poszter

Szekció

Molecular Sciences - Posters K

Language of the presentation

English

Preferred session

Molecular Sciences

Összefoglaló szövege

The CFTR chloride ion channel consists of two pore-forming transmembrane domains, two ATP binding / hydrolyzing cytosolic nucleotide-binding domains driving channel gating, and a cytosolic regulatory (R) domain. The catalytic subunit of PKA binds to the R domain and phosphorylates it, causing reversible and irreversible channel activation. CFTR mutations can cause cystic fibrosis (CF), a devastating disease. ΔF508, the most common CF mutation impairs maturation and gating of the channel, while G551D disrupts ATP-dependent channel gating. Importantly, PKA-dependent activation of these mutants is reportedly also defective. Since the stimulatory effect of the FDA-approved potentiator ivacaftor depends on phosphorylation of CFTR, understanding the impairment of the CFTR-PKA interaction in these mutants is of great significance. In inside-out patch-clamp recordings, we studied the effects of PKA-binding and phosphorylation on channel activation by using an ATP analog that supports CFTR gating but does not support phosphorylation by PKA, and assessed the rates and fractional amplitudes of reversible/irreversible activation in mutant and wild-type (WT) CFTR. The phosphorylation rate of both mutants was comparable to that of WT channels. Importantly, the relative effect of binding is significantly greater for both mutants compared to WT channels, suggesting that the effect of phosphorylation on channel activation is impaired in ΔF508 and G551D CFTR. In the presence of ivacaftor plus elexacaftor reversible activation is still substantial for both unphosphorylated and phosphorylated G551D and for unphosphorylated ΔF508, but small for phosphorylated ΔF508 CFTR channels.

Supported by the ÚNKP-22-3-II New National Excellence Program of the Ministry for Innovation and Technology from the source of the National Research, Development and Innovation Fund.

University and Doctoral School

Semmelweis University, Doctoral School of Molecular Medicine

Supervisor

László Csanády

Publication of my abstract

I do not give consent to the publication of my abstract on the website of the congress.

Kind

Szabad

Status

elfogadva

Accepted presentation method

poszter

Előadás fájl jóváhagyás

nem rendelkezett róla

Előadó

6065

Start

11:06

End

11:11

Authors (legacy)

Márton A Simon, László Csanády
Department of Biochemistry, Semmelweis University