After post degree studies (1973, Biophysics - Biology, Summa-cum-laude) at the University of Milano, DiFrancesco joined in 1976 first the Physiological Laboratory in Cambridge and then, from 1977 to 1980, the Oxford Laboratory of Physiology, working with Denis Noble's team. Here, he and collaborators first described the "funny" (If, or “pacemaker”, or hyperpolarization-activated) current, proposing a new theory for the generation of spontaneous activity of the heart and adrenaline-induced rhythm acceleration.[2] The discovery of the “funny” current and the new proposal of a cardiac pacemaking model raised keen interest in the scientific community and was followed by a fast-increasing number of studies investigating its properties.[3][8][9] These studies eventually led to developments of pharmacological and clinical relevance.[10] As well as in cardiomyocytes, it opened a new field of research in neurons, where a similar current (hyperpolarization activated Ih) was described soon after the cardiac If.[5][11]
The funny current and the new interpretation of cardiac pacemaking
By identifying in 1979 the If ("funny") pacemaker current in the sinus node, Dario DiFrancesco challenged the prevailing theory and proposed a novel mechanism to explain the origin of cardiac rhythm. Based on the discovery of the new “funny” channels, carrying an inward (mixed Na+ and K+) current and activating on hyperpolarization, he modified the concept of cardiac pacemaking by demonstrating that the universally accepted “pacemaker” theory of the time, attributed to the deactivation of an outward potassium current (IK2) in Purkinje fibres,[12] was wrong and had to be turned upside-down. He showed that IK2 had been incorrectly interpreted for over a decade as a pure K+ current and was instead a disguised “funny” current, and pacemaking was not due to deactivation of the outward IK2, but to activation of the inward If.[13] These results showed that the mechanism of pacemaker generation in Purkinje fibres and in sinoatrial node cells was the same, allowing for the first time an integrated view of pacemaking in the heart.[3] Following the discovery of If, DiFrancesco published several studies demonstrating its permeability and gating characteristics, its involvement in the autonomic rate control,[14][15][16] and investigated its single-channel properties, providing first evidence for the smallest conductance (1 pS) channel recorded by patch-clamp.[17] Using a macro-patch clamp technique, he showed for the first time that funny channels are directly activated by intracellular cAMP, a mechanism responsible for the If -mediated autonomic modulation of heart rate.[18] The same modulatory mechanism was later confirmed in HCN channels.[4][19][20][21][22] These experimental studies have been complemented by mathematical and modelling analyses demonstrating the role of If in pacemaker rhythm. In 1985, he developed with Denis Noble a theoretical model incorporating the If -based model of pacemaking and other new experimental results.[23] The model allowed to interpret all experimental data, and represented the paradigm from which subsequent cellular models of the heart were developed. The 1985 model paper was selected in 2015 by the Royal Society, London, as one of the 33 most influential articles published by the Philosophical Transactions of the Royal Society in the 350 years since its foundation in 1665.[24][25][26][27]
HCN channels
Following their cloning,[4][28] DiFrancesco contributed to the molecular biological characterization of the hyperpolarization-activated, cyclic nucleotide-gated (HCN) family of channels responsible for If, analyzing their biochemical and pharmacological regulations.[9][29] A blocker of the funny/HCN channels (ivabradine) approved in 2005 has proved efficacious in the treatment of coronary artery disease and heart failure by reducing cardiac frequency (and hence metabolic demand).[6][29][30] HCN channels have also been identified as potential drug targets in the nervous system, which can help develop new ivabradine-derived drugs to treat neurological diseases like epilepsy, inflammatory, and neuropathic pain.[31][32][33] Beyond heart and brain, HCN channels are in fact expressed in a much larger number of systems/organs than previously thought, where their action is still under investigation[34] and where development of HCN isoform-specific drugs could help clarify their functional roles.
Career
1973–1974 - Teaching and research fellowship, Institute of General Physiology, Univ. Milano
1975–1980 - Research assistant, Institute of General Physiology, Univ. Milano
1976 - Postdoctoral fellow in Cambridge, The Physiological Laboratory (R.D. Keynes)
1977–1978 - Postdoc in cardiac electrophysiology in Oxford, Laboratory of Physiology (Denis Noble)
1979–1980 - Wellcome Trust Fellowship at Oxford University Laboratory of Physiology
From 1978 - Visiting scientist for short periods in various university laboratories of physiology (Homburg/Saar, Paris XI, Tours)
1981–1986 - Assistant professor, Dept. of General Physiology and Biochemistry, Univ. Milano
1986–2018 - Professor of physiology, Department of General Physiology and Biochemistry, then Department of Biosciences, University of Milano
1990–1996 - Periodically, visiting scientist and consultant, Department of Pharmacology of Columbia University, New York (Richard Robinson, Mike Rosen)
