MBExC Online Lecture

Chair: Stephan E. Lehnart

Steven Marx, M.D., Professor of Medicine from the Department of Molecular Pharmacology and Therapeutics, Columbia University Irving Medical Center, New York, NY, USA will talk about “Unraveling the mechanisms of fight or flight: it’s all about the neighborhood”.

Abstract: Increased heart rate and contractility of the cardiac ‘fight-or-flight’ response is dependent upon increased entry of calcium into cardiomyocytes. How activation of the sympathetic nervous system modulates calcium influx has been debated since the 1970s. In a series of papers published in Circulation Research, PNAS, JCI and Nature, Steven Marx’s laboratory has solved this mystery. Using innovative approaches, they demonstrated that adrenergic regulation of calcium influx in heart persisted in transgenic mice expressing channels with alanine-substitutions of all of nearly 90 potential PKA phosphorylation sites, overturning long-accepted dogma. Utilizing state-of-the art proximity proteomics and comparing neighboring proteins under stimulating and resting states, Steven Marx identified a small G-protein, Rad, as the long sought-after link to PKA-mediated activation of calcium channels. In the end, the underlying mechanism turns out to be simple and elegant – at baseline, Rad inhibits cardiac calcium channel activity, while PKA phosphorylation of Rad causes it to leave the vicinity of the calcium channel, thereby preventing it from inhibiting the channel. Furthermore, expression of Rad or its homologue Rem imparts stimulation of CaV1.3 and CaV2.2 by PKA, revealing an evolutionarily conserved mechanism that confers adrenergic modulation upon voltage-gated calcium channels expressed in heart, neuroendocrine cells and neurons.

Subsequent to the lecture a “Meet-the-speaker” will be arranged for the members of the MBExC and Hertha Sponer College.