Key result
GNB2 variant increases I_K,ACh density and slows cardiomyocyte pacing rate upon GIRK stimulation.
Why the study?
The p.Arg52Leu variant in GNB2 is associated with sinus node dysfunction and atrioventricular block, but its functional effects in patient-derived hiPSC-CMs had not been validated.
Does the p.Arg52Leu GNB2 variant cause a gain-of-function in I K,ACh density upon GIRK stimulation in patient-derived hiPSC-CMs, and can it be rescued by I K,ACh blockers?
Does the p.Arg52Leu GNB2 variant cause a gain-of-function in I K,ACh density upon GIRK stimulation in patient-derived hiPSC-CMs, and can it be rescued by I K,ACh blockers?
The p.Arg52Leu GNB2 variant causes a gain-of-function in GIRK channels upon stimulation, leading to a bradycardic phenotype in patient-derived cardiomyocytes that can be pharmacologically rescued by I K,ACh blockers.
Provides mechanistic support for bradycardia in variant carriers; leaves open whether selective I_K,ACh blockade will translate clinically.
Background Initially discovered and published in 2017, the heterozygous mutation (p.Arg52Leu) in the GNB2 gene is associated with sinus node dysfunction (SND) and atrioventricular block (AVB). Electrophysiological characterization using heterologous expression systems has demonstrated that this R52L GNB2 variant results in a larger G-protein–activated K + (GIRK/I K, ACh ) current. So far, this has not been functionally validated in patient-derived disease modelling using human induced pluripotent stem cell-derived cardiomyocytes (CM). Methods Here, we differentiated CMs derived from human induced pluripotent stem cells (hiPSC-CMs) of a patient carrying the pathogenic p.Arg52Leu GNB2 variant (hiPSC R52L -CMs) and compared electrophysiological properties with those of two unrelated healthy hiPSC-CMs control lines. Retinoic acid (RA) treatment during the differentiation was used to generate hiPSC-CMs with robust acetylcholine-activated K + currents (I K, ACh ). Results Patch-clamp experiments demonstrated that without GIRK channel stimulation the maximal diastolic potential (MDP) and spontaneous pacing rate did not differ between mutant and control cell lines and, moreover, a constitutively active I K, ACh was not observed. Upon stimulation of GIRK channels with carbachol (CCh), hiPSC R52L -CMs displayed an increased I K, ACh density, a more hyperpolarized MDP and a slower spontaneous activity as compared to both control hiPSC-CMs cell lines, thus explaining the bradycardia reported from patients carrying the R52L GNB2 variant. Application of the specific I K, ACh blocker XAF-1407 rescued the phenotype. Conclusion The reported, mutant GNB2 in patient-derived CMs is associated with a gain-of function upon GIRK channel stimulation and thereby a larger I K, ACh , which could be potentially targeted and rescued by I K, ACh blockers. Clinical trial number not applicable.
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Verkerk et al. (2026) studied Sinus node dysfunction (SND). p.Arg52Leu GNB2 variant vs. Unrelated healthy hiPSC-CMs control lines was evaluated on Maximal diastolic potential (MDP), spontaneous pacing rate, and I_K,ACh density upon GIRK channel stimulation. The p.Arg52Leu GNB2 variant in patient-derived cardiomyocytes results in an increased I_K,ACh density, a more hyperpolarized maximal diastolic potential, and slower spontaneous activity upon GIRK channel stimulation.
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