Novel insights into IKur modulation by Lgi3-4: Implications in atrial fibrillation
Novel insights into IKur modulation by Lgi3-4: Implications in atrial fibrillation
Socuellamos, P. G.; Macias, A.; de Benito-Bueno, A.; Cruz, F. M.; Redondo-Moya, M.; Coronado, M. J.; Ramil, E.; Rosado, S.; Rios-Rosado, E. C.; Valencia-Avezuela, M.; de Andres-Delgado, L.; Blazquez Gonzalez, J. A.; Forteza-Gil, A.; Gutierrez-Rodriguez, M.; Jalife, J.; Valenzuela, C.
AbstractBackground: Patients with atrial fibrillation (AF) exhibit a reduction in the ultrarapid outward potassium current (IKur) conducted by Kv1.5 channels. Ion channels are modulated by regulatory subunits, forming channelosomes. One such regulatory family are leucine-rich glioma-inactivated proteins (Lgi1-4), which interact with and modulate Kv1 in neurons. However, their impact in the heart remains unknown. We investigated the role of Lgi proteins in cardiac electrophysiology, focusing on IKur, and their contribution to the pathophysiology of AF. Methods: We used three complementary biological systems, including cell lines, AAV-mediated cardiac-specific Lgi4 mice (Lgi4 mice), and human samples from patients in sinus rhythm (SR) and AF. Our multidisciplinary approach included immunolocalization, patch-clamp, surface ECG, intracardiac stimulation, and molecular biology techniques. Results: Only Lgi3 and Lgi4 were expressed in human heart. In human atrium and heterologous cells, Lgi3 and Lgi4 interacted with Kv1.5 channels. In HEK293 cells, Lgi3-4 impaired Kv1.5/Kv{beta} association, partially reversing the Kv{beta}-induced N-type inactivation and reducing IKur amplitude. On surface ECG, the QRS interval was prolonged, and impulse conduction was impaired in Lgi4 mice compared to control. In isolated ventricular cardiomyocytes from Lgi4 mice, early action potential repolarization was prolonged compared to control. These results correlated with the reduced Kv1.5 membrane expression and IKur density observed in Lgi4 cardiomyocytes and HEK293 cells. Notably, Lgi4 protein expression was lower in atrial tissue from patients with AF than SR. The reduction of Lgi4 in AF was associated with an altered colocalization with Kv1.5 channels, suggesting potential disruptions in their functional interactions. Conclusions: Lgi3-4 proteins are new components of KV1.5 channelosome. They modulate IKur by interfering with Kv1.5 interaction with Kv{beta}. Importantly, Lgi4 is dysregulated differently in paroxysmal versus permanent AF. The results improved the understanding of this most common type of arrhythmia and identified Lgi proteins as a new potential target for AF treatment.