Physical Address

304 North Cardinal St.
Dorchester Center, MA 02124

Function and Dysfunction of Ion Channel Membrane Trafficking and Posttranslational Modification

Introduction Over the course of the average human life span, the heart will beat more than 2 billion times. Moreover, the cardiovascular system must be essentially failproof across the decades of human life as any loss of function even for only minutes may be fatal. To ensure robust cardiac function, the heart has evolved elaborate pathways to regulate excitability across diverse cardiac cell types (sinus node…

The Intercalated Disc: A Molecular Network That Integrates Electrical Coupling, Intercellular Adhesion, and Cell Excitability

Introduction And Historical Perspective A heartbeat results from the added output of millions of cells that contract in synchrony. To achieve this function, complex molecular networks work in concert with exquisite temporal precision. The accurate timing of the molecular events demands a comparable precision on the location of each molecule within the cell. Indeed, molecular networks organize within well-confined microdomains, where physical proximity allows for prompt…

Reciprocity of Cardiac Sodium and Potassium Channels in the Control of Excitability and Arrhythmias

Acknowledgments We thank Ricardo Caballero for comments on the manuscript. This work was supported by a 2018 Health Research Grant from “la Caixa” Foundation; CNIC Intramural Grant Severo Ochoa Program (IGP-SO); R01 Grant HL122352 from the U.S. National Heart Lung and Blood Institute (J.J.) and the Leducq Foundation (J.J.), as well as Ministerio de Economía, Industria y Competitividad (SAF2017-88116-P) and Comunidad de Madrid (S2017/BMD-3738; E.D.). Introduction…

Macromolecular Complexes and Cardiac Potassium Channels

Introduction In the heart, the main repolarizing currents are carried by potassium ions. A number of potassium currents shape and control the action potential (AP). The inward rectifier K + current is crucial for maintaining the membrane potential near the equilibrium potential for potassium, –90 mV during diastole. The voltage-dependent outward currents regulate the activation and termination of the plateau phase of the AP, and the…

Connecting Cardiac Excitation to the Atomic Interactions of Ion Channels

Introduction The generation of the action potential is based on an exquisite orchestration of many ion channels acting in concert with a balance of depolarizing and repolarizing forces such that the system (the heart) generates an impulse and returns to its baseline. Despite decades of research into ion channel biology, it is currently impossible to predict how genetic variants in key ion channels will impact the…

Microdomain Interactions of Macromolecular Complexes and Regulation of the Sodium Channel Na V 1.5

Acknowledgment Dr. Abriel’s work is supported by a grant of the Swiss National Science Foundation (310030_184783) and the University of Bern. Na V 1.5 and Interacting Proteins Na V 1.5 has been shown to interact with a growing list of proteins ( Fig. 18.1 ; Table 18.1 ). Mutations in genes encoding Na V 1.5 and several interacting proteins have been found in patients with inherited…

Ion Channel Trafficking in the Heart

Overview of Ion Channel Trafficking in the Heart A remarkable aspect of cardiac ion channel biology is that individual ion channels have half-lives on the order of hours. For example, Cx43 gap junction proteins have a half-life of 1 to 3 hours, , and calcium channels have half-lives that are reported to be 2 to 8 hours. , The short life span of ion channels suggests…

Excitation–Contraction Coupling

Excitation-Contraction Coupling and Relationship to Action Potentials Cardiac excitation-contraction coupling (ECC) is the process by which the electrical activation of cardiac myocytes leads to the activation of contraction. – In the broadest sense, ECC refers to everything from the initial membrane depolarization through the action potential (AP) to the activation of the Ca 2+ transient, including how the myofilaments respond to the Ca 2+ transient to…

Connexins and Pannexins in Cardiovascular Disease

Acknowledgments We thank Drs. S. Morel, F. Molica, and O. Rusiecka for help with the preparation of figures and critical proofreading. The work of B.R.K. is supported by the Swiss National Science Foundation. Background Connexins (Cxs) and pannexins (Panxs) have been implicated in a variety of cardiovascular diseases. Although their causal involvement in disease development has been clear in the case of certain mutations, protein function,…

Stretch-Activated Potassium Channels in the Human Heart: Pathophysiologic and Clinical Significance

Acknowledgments We are grateful to Professors Ursula Ravens, Alexander Quinn, and Niels Decher for helpful comments on the manuscript. We thank the European Research Council, the German Research Foundation, and the Ministry of Science, Research and the Arts of the Federal State of Baden-Württemberg for their generous support of research in our labs. The authors are members of the German Collaborative Research Centre SFB1425. Introduction: Mechanics…

Functional Characterization of Ion Channel Gene Variants in Sudden Unexplained Natural Death

Sudden Unexplained Death Sudden unexplained death (SUD) is defined here as the death of an individual that remains unexplained after a thorough investigation, which often includes gross and microscopic examination by the medical examiners, detailed cardiac pathology and neuropathology examinations, laboratory tests (e.g., toxicology and microbiology), and a review of the available medical records. SUD occurs in all age groups from infants in their first year…

Role of Enhancers in Transcriptional Regulation of Cardiac Electrical Activity

Function of the Cardiac Conduction System The electrical activity pattern of the mammalian heart, which depends on coordinated generation and propagation of action potentials, is essential for proper rhythmic contraction of the heart. Action potentials are generated and propagated by the cardiac conduction system (CCS) and working myocardium. The electrical impulse originates from the pacemaker cells in the sinoatrial node (SAN) followed by rapid propagation through…

Molecular Genetics of ATP-Sensitive Potassium Channels in Cardiovascular Diseases

Introduction It has been almost 40 years since Noma first discovered adenosine triphosphate–sensitive potassium channels in cardiac muscle. Members of this channel family were found in skeletal myocytes, pancreatic β cells, neurons, vascular smooth muscle and endothelium, and lymphatic smooth muscle. Although highly expressed in the heart, cardiac K ATP channels are essentially closed under normal conditions and may play little role in shaping normal action…

Regulation of Cardiac Calcium Channels

Overview The superfamily of voltage-gated ion channels is defined by the common ability of the protein to sense transmembrane potential. Voltage-gated ion channels, specifically voltage-gated cation channels, consist of a pore-forming protein (the α-subunit) that shares the general structural plan consisting of six α-helical transmembrane segments and a region of amino acids between transmembrane segments five and six (S5 and S6) that fold from the extracellular…

Computational Modeling and Simulation for Human Cardiac Electrophysiology: From Induced Pluripotent Stem Cell–Derived Cardiomyocytes to Adult Cardiomyocytes

Induced Pluripotent Stem Cell–Derived Cardiomyocytes for Study of Human Cardiac Electrophysiology Human Cell Model for Study of Genetics in Health and Disease The study of the human cardiac rhythm has long been limited by the study of fundamental mechanisms in the human heart through approximated models of the heart and its environment. None of the common reductionist experimental approaches allows for study of the cardiac system within…

Gap Junctional Connexin43: Novel Insights from the New Millennium and Their Clinical Implications

Introduction Connexins are the subunit proteins of gap junction (GJ) channels. Connexin43 (Cx43) is the most broadly expressed connexin in the tissues and organs of the human body and the main GJ protein of the heart. , Gap junctions provide a direct, gated pathway for cytoplasmic coupling between cells. This capacity is the basis of the long-standing consensus view on the main significance of connexins and…

Organellar Ion Channels and Transporters

Introduction: Structural and Molecular Bases of Mitochondrial Ion Channel Function Although ion channels and transporters are important modulators to mediate the ion flux across the plasma membrane in various cell types, including cardiomyocytes, they are also expressed on intracellular membranes to regulate various organellar and cellular functions. These intracellular membrane structures include the endoplasmic reticulum (ER)/sarcoplasmic reticulum (SR), Golgi apparatus, endosomes, lysosomes, mitochondria, nucleus, chloroplasts, and…

Structural and Molecular Bases of Sarcoplasmic Reticulum Ion Channel Function

Acknowledgment The authors acknowledge support provided by the American Heart Association (SDG 17SDG33410716 to BL) and the National Institutes of Health (grants RO1 HL074045, HL063043, and HL138579 to S.G.; R00 HL127299 and AHA 19TPA34910191 to P.B.R.). Structural Arrangement of the Sarcoplasmic Reticulum The sarcoplasmic reticulum (SR) is a membrane-delimited intracellular organelle that spans the sarcomere and wraps up the contractile myofilaments in the striated muscle of…

Mammalian Calcium Pumps in Health and Disease

AcknowledgmentS We are grateful to Dr. C. Toyoshima (Tokyo, Japan) for providing the image of the SERCA pump structure in Fig. 5.2 and the illustrations in Fig. 5.3 , Dr. L. Raeymaekers (Leuven, Belgium) for providing the structural model of the SPCA pump in Fig. 5.4 , and Dr. S. Pantano (Montevideo, Uruguay) for providing the model of PMCA in Fig. 5.5 . The authors have…

Molecular Regulation of Cardiac Inward Rectifier Potassium Channels

Introduction Potassium channels play a critical role in modulating cardiac excitability via their effects on the resting membrane potential and on the action potential waveform. The potassium channel family is diverse and comprises the voltage-gated, inwardly rectifying (Kir), small-conductance calcium-activated, and two-pore domain K + channel subfamilies. The currents that flow through Kir channels include the inward rectifier (I K1 ), the acetylcholine-activated (I K(Ach) ),…