Dr. Lederer, an innovator in cardiac research, has and continues to make fundamental discoveries that change our view of biology and medicine. As a student at Yale , he discovered a Ca2+ -activated membrane current that is now known to be the primary membrane current underlying Ca2+ -dependent arrhythmias. He and his co-workers then went on to make important discoveries in how protons affect cellular signaling, how Na+ is linked to Ca2+ signaling in excitable cells, how the Na+/Ca2+ exchanger works as an ion transporter and charge carrier, how the spatial organization of these proteins at the nanoscopic level underlie their signaling. This understanding enabled Lederer and his colleagues to discover and characterize Ca2+ sparks in heart. Ca2+ sparks, the primary unit of Ca2+ release in the heart, are normally triggered by Ca2+ influx during the cardiac electrical signal, the action potential, and thus link excitation to contraction. In diverse pathological conditions, Lederer and co-workers also have shown that Ca2+ sparks are the essential component of Ca2+ leak in the heart that produce Ca2+ waves in single cells and arrhythmias in the heart. Importantly, these Ca2+ signals underlie the arrhythmogenic current discovered by Lederer as a student. Lederer and colleagues recently linked Ca2+ sparks, Ca2+ leak and the arrhythmogenic current to diverse genetic and acquired arrhythmias. The leak was shown to be due to both Ca2+ sparks and the ryanodine receptors (RyR2), the individual SR Ca2+ release channels. Ca2+ sparks are produced when a cluster of RyR2 are activated as an ensemble. Significantly, as this work was unfolding, Lederer and his co-workers also demonstrated that the principles of local Ca2+ signaling identified and characterized as Ca2+ sparks in heart were a general phenomenon in biology, particularly in muscle. Ca2+ sparks were demonstrated in amphibian skeletal muscle and in vascular smooth muscle, although the function in each tissue was distinct. In vascular smooth muscle, for example, Ca2+ sparks and local Ca2+ elevation were shown to underlie vascular relaxation (but not contraction). These discoveries have led to critical new discoveries on how blood flow is regulated in diverse excitable tissues including the brain (i.e. neurovascular coupling). In heart, the Ca2+ spark dependent [Ca2+]i transient produces systolic contraction with muscle cell shortening and diastolic relaxation with muscle cell re-lengthening and stretching. While examining this process, Lederer and co-workers discovered a key new signaling pathway in the heart that links cellular mechanical behavior to Ca2+ signaling. The new signaling pathway, called "X-ROS signaling", is activated by diastolic cellular stretching linked by the cytoskeleton to membrane-bound NADPH oxidase (NOX2) located near the cluster of RyR2 SR Ca2+ release channels (within 10's of nanometers). During diastolic filling, microtubules that are linked to NOX2 proteins activate the enzyme that produces local reactive oxygen species (ROS), and this local ROS leads to an increase in the spark rate and thus "tunes" the [Ca2+]i transient. Recent work now also focuses on cardiac mitochondrial biology. Lederer has thus made surprising discoveries that have fundamentally changed the way we see and think about signaling in biology and medicine.
Lederer was raised in Honolulu, Hawaii, attended Harvard University as an undergraduate and Yale University for medical and graduate school, working with Richard W. Tsien in Physiology for his PhD training. After medical internship at the University of Washington in Seattle, he received a British-American Heart Fellowship to work with Denis Noble at Oxford University. He is now Director of the Center for Biomedical Engineering and Technology and Professor of Physiology at the University of Maryland School of Medicine in Baltimore, Maryland, USA.