Popeye-domain-containing proteins modulate the voltage-gated cardiac sodium channel Nav1.5
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Popeye-domain-containing proteins modulate the voltage-gated cardiac sodium channel Nav1.5. / Rinné, Susanne; Kiper, Aytug K.; Jacob, Ralf; Ortiz-Bonnin, Beatriz; Schindler, Roland F.R.; Fischer, Sabine; Komadowski, Marlene; deMartino, Emilia; Schäfer, Martin K.-H.; Cornelius, Tamina; Fabritz, Larissa; Helker, Christian S.M.; Brand, Thomas; Decher, Niels.
In: ISCIENCE, Vol. 27, No. 5, 17.05.2024, p. 109696.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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T1 - Popeye-domain-containing proteins modulate the voltage-gated cardiac sodium channel Nav1.5
AU - Rinné, Susanne
AU - Kiper, Aytug K.
AU - Jacob, Ralf
AU - Ortiz-Bonnin, Beatriz
AU - Schindler, Roland F.R.
AU - Fischer, Sabine
AU - Komadowski, Marlene
AU - deMartino, Emilia
AU - Schäfer, Martin K.-H.
AU - Cornelius, Tamina
AU - Fabritz, Larissa
AU - Helker, Christian S.M.
AU - Brand, Thomas
AU - Decher, Niels
PY - 2024/5/17
Y1 - 2024/5/17
N2 - Popeye domain containing (POPDC) proteins are predominantly expressed in the heart and skeletal muscle, modulating the K2P potassium channel TREK-1 in a cAMP-dependent manner. POPDC1 and POPDC2 variants cause cardiac conduction disorders with or without muscular dystrophy. Searching for POPDC2-modulated ion channels using a functional co-expression screen in Xenopus oocytes, we found POPDC proteins to modulate the cardiac sodium channel Nav1.5. POPDC proteins downregulate Nav1.5 currents in a cAMP-dependent manner by reducing the surface expression of the channel. POPDC2 and Nav1.5 are both expressed in different regions of the murine heart and consistently POPDC2 co-immunoprecipitates with Nav1.5 from native cardiac tissue. Strikingly, the knock-down of popdc2 in embryonic zebrafish caused an increased upstroke velocity and overshoot of cardiac action potentials. The POPDC modulation of Nav1.5 provides a new mechanism to regulate cardiac sodium channel densities under sympathetic stimulation, which is likely to have a functional impact on cardiac physiology and inherited arrhythmias.
AB - Popeye domain containing (POPDC) proteins are predominantly expressed in the heart and skeletal muscle, modulating the K2P potassium channel TREK-1 in a cAMP-dependent manner. POPDC1 and POPDC2 variants cause cardiac conduction disorders with or without muscular dystrophy. Searching for POPDC2-modulated ion channels using a functional co-expression screen in Xenopus oocytes, we found POPDC proteins to modulate the cardiac sodium channel Nav1.5. POPDC proteins downregulate Nav1.5 currents in a cAMP-dependent manner by reducing the surface expression of the channel. POPDC2 and Nav1.5 are both expressed in different regions of the murine heart and consistently POPDC2 co-immunoprecipitates with Nav1.5 from native cardiac tissue. Strikingly, the knock-down of popdc2 in embryonic zebrafish caused an increased upstroke velocity and overshoot of cardiac action potentials. The POPDC modulation of Nav1.5 provides a new mechanism to regulate cardiac sodium channel densities under sympathetic stimulation, which is likely to have a functional impact on cardiac physiology and inherited arrhythmias.
KW - ion channel
KW - Nav1.5
KW - POPDC
KW - Popeye-domain-containing proteins
KW - sodium channel
U2 - 10.1016/j.isci.2024.109696
DO - 10.1016/j.isci.2024.109696
M3 - SCORING: Journal article
C2 - 38689644
VL - 27
SP - 109696
JO - ISCIENCE
JF - ISCIENCE
SN - 2589-0042
IS - 5
ER -