Identification of cardiac ion channel protein networks and their signature in the human electrocardiogram

ABSTRACT: Protein-protein interactions are essential for normal cellular processes and signaling events. Defining these interaction networks is therefore crucial for understanding complex cellular functions and interpretation of disease-associated gene variants. We need to build a comprehensive picture of the interactions, their affinities and interdependencies in the specific organ and cell-type to understand hitherto poorly understood signaling mechanism through ion channels and to begin their mechanistic studies. Here, we experimentally identify the ensemble of interacting partners for 13 types of ion channel in murine cardiac tissue to understand their role in cardiomyocyte electrophysiology. Of these, we validated the functional importance of 10 novel interactors on cardiac electrophysiology through genetic knockouts in zebrafish, super resolution microscopy, and patch clamp experiments. Furthermore, we establish a computational framework to reconstruct human cardiomyocyte ion channel networks from deep proteome mapping of human heart tissue and human heart single-cell gene-expression data. Finally, we integrate the ion channel interactome with human population genetics data to identify proteins that influence the electrocardiogram (ECG). The combined channel network is enriched for proteins influencing the ECG; with 44% of the network proteins significantly associated with an ECG phenotype. Altogether, we comprehensively define the interactomes of 13 major cardiac ion channels, contextualize their relevance to human electrophysiology including impact on the ECG, and validate the functional roles of ten novel interactors, thereby creating a roadmap for our understanding of how ion channel interactomes regulate cardiac electrophysiology.

INSTRUMENT(S): Q Exactive HF

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Heart

SUBMITTER: Svetlana Maurya  

LAB HEAD: Alicia Lundby

PROVIDER: PXD028021 | Pride | 2023-09-18

REPOSITORIES: Pride