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Cardiac ion channel current modulation by the CFTR inhibitor GlyH-101

Author:
Barman, Palash P., Choisy, Stéphanie C.M., Gadeberg, Hanne C., Hancox, Jules C., James, Andrew F.
Source:
Biochemical and biophysical research communications 2011 v.408 no.1 pp. 12-17
ISSN:
0006-291X
Subject:
calcium channels, cardiomyocytes, chlorides, cystic fibrosis, electrophysiology, heart, inhibitory concentration 50, potassium, protein kinases, rabbits, sodium
Abstract:
The role in the heart of the cardiac isoform of the cystic fibrosis transmembrane conductance regulator (CFTR), which underlies a protein kinase A-dependent Cl⁻ current (ICₗ.PKA) in cardiomyocytes, remains unclear. The identification of a CFTR-selective inhibitor would provide an important tool for the investigation of the contribution of CFTR to cardiac electrophysiology. GlyH-101 is a glycine hydrazide that has recently been shown to block CFTR channels but its effects on cardiomyocytes are unknown. Here the action of GlyH-101 on cardiac ICₗ.PKA and on other ion currents has been established. Whole-cell patch-clamp recordings were made from rabbit isolated ventricular myocytes. GlyH-101 blocked ICₗ.PKA in a concentration- and voltage-dependent fashion (IC₅₀ at +100mV=0.3±1.5μM and at −100mV=5.1±1.3μM). Woodhull analysis suggested that GlyH-101 blocks the open pore of cardiac CFTR channels at an electrical distance of 0.15±0.03 from the external membrane surface. A concentration of GlyH-101 maximally effective against ICₗ.PKA (30μM) was tested on other cardiac ion currents. Inward current at −120mV, comprised predominantly of the inward-rectifier background K⁺ current, IK₁, was reduced by ∼43% (n=5). Under selective recording conditions, the Na⁺ current (INₐ) was markedly inhibited by GlyH-101 over the entire voltage range (with a fractional block at −40mV of ∼82%; n=8). GlyH-101 also produced a voltage-dependent inhibition of L-type Ca²⁺ channel current (ICₐ,L); fractional block at +10mV of ∼49% and of ∼28% at −10mV; n=11, with a ∼−3mV shift in the voltage-dependence of ICₐ,L activation. Thus, this study demonstrates for the first time that GlyH-101 blocks cardiac ICₗ.PKA channels in a similar fashion to that reported for recombinant CFTR. However, inhibition of other cardiac conductances may limit its use as a CFTR-selective blocker in the heart.
Agid:
893862