Dipeptidyl aminopeptidase-like protein 6 regulates the <i>I</i>_Na-<i>I</i>_to balance influencing cardiac electrophysiology and arrhythmogenesis.

Abstract

Dipeptidyl aminopeptidase-like protein 6 (DPP6) is a subunit of the K_v4 channels that carry the transient-outward current (<i>I</i>_to) in cardiac Purkinje cells (PCs) and ventricular myocytes (VMs). <i>DPP6</i> genetic variants have been linked to severe arrhythmia syndromes. Given the influence of other <i>I</i>_to subunits on the Na_v1.5-mediated cardiac sodium current (<i>I</i>_Na), we examined whether DPP6 regulates both <i>I</i>_to and <i>I</i>_Na. We explored the impact of the <i>DPP6</i> missense variants c.821G>A and c.637C>T, segregating in families with long-QT syndrome (LQTS), and c.2252C>T and c.1578G>C, associated with J-wave syndromes (JWSs) and unexplained syncope. In human and mouse heart slices, DPP6 localized within 40 nanometers of Na_v1.5. Functionally, DPP6 reduced <i>I</i>_Na and increased <i>I</i>_to density in transfected Chinese hamster ovary cells. <i>DPP6</i> variants linked to LQTS and JWSs led to a hypo- and hyperinhibition of <i>I</i>_Na, respectively. Conversely, <i>I</i>_to was increased by the JWS variants and decreased by the LQTS variants coexpressed with PC (but not VM) <i>I</i>_to subunits. These findings were validated in human induced pluripotent stem cell-derived cardiomyocytes. In silico modeling of <i>I</i>_Na and <i>I</i>_to data into PC and VM single-cell action potentials, subsequently integrated in two-dimensional tissue simulations, produced steep repolarization gradients for LQTS-c.821G>A versus slowed conduction for JWS-c.2252C>T. Noninvasive electrocardiographic imaging, used for advanced clinical phenotyping, showed dispersed and prolonged repolarization in the <i>DPP6</i> c.821G>A index patient versus right ventricular outflow tract delayed activation of a <i>DPP6</i> c.2252C>T carrier. In conclusion, <i>DPP6</i> variants play an important role in the mutually antagonistic regulation of <i>I</i>_Na and <i>I</i>_to, contributing to cardiac electrophysiology and arrhythmogenesis.