Key result
Gosr2 deficiency increases longitudinal conduction velocity ~20% in mice compared to wild-type controls.
Why the study?
Genome-wide association studies linked the GOSR2 locus with QRS- and QT-intervals, but the role of Membrin in cardiac conduction and sodium channel availability was unclear.
Does Membrin modulation affect cardiac conduction and sodium channel availability in preclinical models?
Does Membrin modulation affect cardiac conduction and sodium channel availability in preclinical models?
Absolute Event Rate: 62% vs 51.86%
p-value: p=0.039
Membrin interacts with NaV1.5 and modulates cardiac conduction, suggesting a role in ion channel trafficking or posttranslational maturation.
May implicate Membrin in NaV1.5-mediated conduction; hypothesis-generating and leaves open translational relevance.
Background Genome-wide association studies have associated a locus spanning GOSR2 with QRS- and QT-interval. GOSR2 encodes Membrin, a protein located at the cis-Golgi, which plays a role in protein trafficking. Altered trafficking of the cardiac sodium channel (NaV1.5), encoded by SCN5A, has been shown to reduce cardiac conduction. Purpose To explore the modulatory role of Membrin on cardiac conduction and sodium channel availability. Methods and results Tandem Affinity Purification in H10 cells (derived from neonatal rat cardiomyocytes) overexpressing the NaV1.5 C-terminus identified Membrin as a putative interactor of NaV1.5. We subsequently confirmed the interaction between NaV1.5 and Membrin by means of a co-immunoprecipitation assay in HEK293A cells that overexpress NaV1.5 and Membrin. To investigate whether Membrin affects cardiac conduction we recorded optical action potentials from the left ventricle (LV) of Langendorff-perfused hearts from Gosr2+/− mice and wild type (WT) littermate controls. Conduction velocity was measured at steady state pacing (cycle length 120ms) and at the minimal possible cycle length (S2min), during S1S2 pacing. Longitudinal conduction velocity was increased in Gosr2+/− mice compared to WT at steady state- (76.44 vs. 67.00 cm/s) as well as at S2min (62.00 vs. 51.86 cm/s, p=0.039, n=10 and 9, resp.). Single cell patch-clamp studies revealed a shortened action potential duration at 90% repolarization at all pacing frequencies (390 vs 342 V/s at 2Hz, p=0.036) in isolated mid-LV cardiomyocytes of Gosr2+/− mice compared to WT. In addition, the maximal upstroke velocity was increased in Gosr2+/− mid-LV cardiomyocytes at frequencies of 6Hz and higher (390 vs 342 V/s at 6Hz, p=0.044). Conclusion Our findings identify Membrin as a novel interacting protein of NaV1.5 and a modulator of cardiac conduction. We propose that Membrin acts through ion channel trafficking or by modulating the posttranslational maturation of ion channels. Funding Acknowledgement Type of funding source: Foundation. Main funding source(s): Leducq foundation
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Offerhaus et al. (2020) studied Cardiac conduction (n=19). Gosr2 haploinsufficiency (Gosr2+/-) vs. Wild type (WT) littermate controls was evaluated on Longitudinal conduction velocity at minimal possible cycle length (S2min) (p=0.039). In a mouse model, Gosr2+/- mice exhibited increased longitudinal conduction velocity at minimal cycle length compared to wild-type controls (62.00 vs. 51.86 cm/s, p=0.039).
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