Dario DiFrancesco

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Dario DiFrancesco (born 10 February 1948)[1] is a Professor Emeritus (Physiology) at the University of Milano. In 1979, he and collaborators discovered the so-called "funny" (or "pacemaker") current in cardiac pacemaker cells,[2] a new mechanism involved in the generation of cardiac spontaneous activity and autonomic regulation of heart rate.[3] That initiated a new field of research in the heart and brain, where hyperpolarization-activated, cyclic nucleotide-gated (HCN) channels, the molecular components of "funny" channels cloned in the late 90's,[4] are today known to play fundamental roles in health and disease.[5] Clinically relevant exploitation of the properties of "funny" channels has developed a channel blocker with specific heart rate-slowing action, ivabradine, marketed for the therapy of coronary artery disease, heart failure and the symptomatic treatment of chronic stable angina.[6]

Dario DiFrancesco is the 2008 recipient of the Grand Prix scientifique de la Fondation Lefoulon-Delalande of the Institute de France.[7]

Biography[edit]

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[edit]

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[edit]

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[edit]

  • 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
  • From 1986 - Periodically, visiting scientist at SUNY - Stony Brook, New York (Ira Cohen)
  • 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)
  • From 1999 - Professor of physiology and biophysics at Vita-Salute University, San Raffaele Hospital, Milano
  • From 2019 - Emeritus professor (physiology), University of Milan

Publications[edit]

Dario DiFrancesco's publication list includes more than 380 articles in academic journals[35] including Nature, Science, Journal of Physiology, Journal of General Physiology, PNAS, Progress in Biophysics & Molecular Biology, Circulation, Circulation Research, New England Journal of Medicine, Journal of Molecular and Cellular Cardiology, European Heart Journal and others.[36]

DiFrancesco's h-index is 78 and the number of citations is higher than 22000 (Google Scholar, 07/2022).[35] He has delivered more than 220 talks to invited presentations/congresses/named lectures.[37] He is a member of the Academia Europaea, of the Istituto Lombardo- Accademia di Scienze e Lettere and a Fellow of the IUPS Academy.[38][39][40]

Awards and honours[edit]

References[edit]

  1. ^ "Dario DiFrancesco: Curriculum vitae" (PDF).
  2. ^ a b Brown, H. F.; Difrancesco, D.; Noble, S. J. (July 1979). "How does adrenaline accelerate the heart?". Nature. 280 (5719): 235–236. Bibcode:1979Natur.280..235B. doi:10.1038/280235a0. PMID 450140. S2CID 4350616.
  3. ^ a b c Noble, D (1 August 1984). "The surprising heart: a review of recent progress in cardiac electrophysiology". The Journal of Physiology. 353: 1–50. doi:10.1113/jphysiol.1984.sp015320. PMC 1193291. PMID 6090637. S2CID 27189462.
  4. ^ a b c Santoro, Bina; Liu, David T; Yao, Huan; Bartsch, Dusan; Kandel, Eric R; Siegelbaum, Steven A; Tibbs, Gareth R (May 1998). "Identification of a Gene Encoding a Hyperpolarization-Activated Pacemaker Channel of Brain". Cell. 93 (5): 717–729. doi:10.1016/s0092-8674(00)81434-8. ISSN 0092-8674. PMID 9630217. S2CID 10265917.
  5. ^ a b Robinson, Richard B.; Siegelbaum, Steven A. (1 March 2003). "Hyperpolarization-Activated Cation Currents: From Molecules to Physiological Function". Annual Review of Physiology. 65: 453–480. doi:10.1146/annurev.physiol.65.092101.142734. PMID 12471170.
  6. ^ a b DiFrancesco, Dario; Camm, John A. (1 August 2004). "Heart Rate Lowering by Specific and Selective If Current Inhibition with Ivabradine". Drugs. 64 (16): 1757–1765. doi:10.2165/00003495-200464160-00003. PMID 15301560. S2CID 8484872.
  7. ^ a b "Accueil". Fondation Lefoulon-Delalande (in French). Retrieved 2022-07-01.
  8. ^ DiFrancesco, D. (1993). "Pacemaker mechanisms in cardiac tissue". Annual Review of Physiology. 55: 455–472. doi:10.1146/annurev.ph.55.030193.002323. ISSN 0066-4278. PMID 7682045.
  9. ^ a b Noble, Denis (November 2021). "The surprising heart revisited: an early history of the funny current with modern lessons". Progress in Biophysics and Molecular Biology. 166: 3–11. doi:10.1016/j.pbiomolbio.2020.07.010. ISSN 1873-1732. PMID 32861776. S2CID 221383480.
  10. ^ DiFrancesco, Dario (2010-02-19). "The role of the funny current in pacemaker activity". Circulation Research. 106 (3): 434–446. doi:10.1161/CIRCRESAHA.109.208041. ISSN 1524-4571. PMID 20167941. S2CID 2722490.
  11. ^ Pape, H. C. (1996). "Queer current and pacemaker: the hyperpolarization-activated cation current in neurons". Annual Review of Physiology. 58: 299–327. doi:10.1146/annurev.ph.58.030196.001503. ISSN 0066-4278. PMID 8815797.
  12. ^ Noble, D.; Tsien, R. W. (March 1968). "The kinetics and rectifier properties of the slow potassium current in cardiac Purkinje fibres". The Journal of Physiology. 195 (1): 185–214. doi:10.1113/jphysiol.1968.sp008454. ISSN 0022-3751. PMC 1557911. PMID 5639799.
  13. ^ DiFrancesco, D. (May 1981). "A new interpretation of the pace-maker current in calf Purkinje fibres". The Journal of Physiology. 314: 359–376. doi:10.1113/jphysiol.1981.sp013713. ISSN 0022-3751. PMC 1249439. PMID 6273533.
  14. ^ DiFrancesco, D. (May 1981). "A study of the ionic nature of the pace-maker current in calf Purkinje fibres". The Journal of Physiology. 314: 377–393. doi:10.1113/jphysiol.1981.sp013714. ISSN 0022-3751. PMC 1249440. PMID 6273534.
  15. ^ DiFrancesco, D.; Ferroni, A.; Mazzanti, M.; Tromba, C. (August 1986). "Properties of the hyperpolarizing-activated current (if) in cells isolated from the rabbit sino-atrial node". The Journal of Physiology. 377: 61–88. doi:10.1113/jphysiol.1986.sp016177. ISSN 0022-3751. PMC 1182823. PMID 2432247.
  16. ^ DiFrancesco, D.; Ducouret, P.; Robinson, R. B. (1989-02-03). "Muscarinic modulation of cardiac rate at low acetylcholine concentrations". Science. 243 (4891): 669–671. Bibcode:1989Sci...243..669D. doi:10.1126/science.2916119. ISSN 0036-8075. PMID 2916119.
  17. ^ DiFrancesco, D. (December 4–10, 1986). "Characterization of single pacemaker channels in cardiac sino-atrial node cells". Nature. 324 (6096): 470–473. Bibcode:1986Natur.324..470D. doi:10.1038/324470a0. ISSN 0028-0836. PMID 2431323. S2CID 6180447.
  18. ^ DiFrancesco, D.; Tortora, P. (1991-05-09). "Direct activation of cardiac pacemaker channels by intracellular cyclic AMP". Nature. 351 (6322): 145–147. Bibcode:1991Natur.351..145D. doi:10.1038/351145a0. ISSN 0028-0836. PMID 1709448. S2CID 4326191.
  19. ^ Viscomi, C.; Altomare, C.; Bucchi, A.; Camatini, E.; Baruscotti, M.; Moroni, A.; DiFrancesco, D. (2001-08-10). "C terminus-mediated control of voltage and cAMP gating of hyperpolarization-activated cyclic nucleotide-gated channels". The Journal of Biological Chemistry. 276 (32): 29930–29934. doi:10.1074/jbc.M103971200. ISSN 0021-9258. PMID 11397812.
  20. ^ Wainger, B. J.; DeGennaro, M.; Santoro, B.; Siegelbaum, S. A.; Tibbs, G. R. (2001-06-14). "Molecular mechanism of cAMP modulation of HCN pacemaker channels". Nature. 411 (6839): 805–810. Bibcode:2001Natur.411..805W. doi:10.1038/35081088. ISSN 0028-0836. PMID 11459060. S2CID 575481.
  21. ^ Accili, E. A.; Proenza, C.; Baruscotti, M.; DiFrancesco, D. (February 2002). "From funny current to HCN channels: 20 years of excitation". News in Physiological Sciences. 17: 32–37. doi:10.1152/physiologyonline.2002.17.1.32. ISSN 0886-1714. PMID 11821534. S2CID 6389152.
  22. ^ Biel, Martin; Wahl-Schott, Christian; Michalakis, Stylianos; Zong, Xiangang (July 2009). "Hyperpolarization-activated cation channels: from genes to function". Physiological Reviews. 89 (3): 847–885. doi:10.1152/physrev.00029.2008. ISSN 0031-9333. PMID 19584315.
  23. ^ DiFrancesco, D.; Noble, D. (1985-01-10). "A model of cardiac electrical activity incorporating ionic pumps and concentration changes". Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences. 307 (1133): 353–398. Bibcode:1985RSPTB.307..353D. doi:10.1098/rstb.1985.0001. ISSN 0962-8436. PMID 2578676.
  24. ^ "History of Philosophical Transactions | Royal Society". royalsociety.org. Retrieved 2022-07-18.
  25. ^ "Philosophical Transactions of the Royal Society B: Biological Sciences: Vol 370, No 1666". Philosophical Transactions of the Royal Society B: Biological Sciences. Retrieved 2022-07-18.
  26. ^ Dibb, Katharine; Trafford, Andrew; Zhang, Henggui; Eisner, David (2015-04-19). "A model model: a commentary on DiFrancesco and Noble (1985) 'A model of cardiac electrical activity incorporating ionic pumps and concentration changes'". Philosophical Transactions of the Royal Society B: Biological Sciences. 370 (1666): 20140316. doi:10.1098/rstb.2014.0316. PMC 4360121. PMID 25750236.
  27. ^ "a conversation with dario difrancesco and denis noble".
  28. ^ Moroni, A.; Gorza, L.; Beltrame, M.; Gravante, B.; Vaccari, T.; Bianchi, M. E.; Altomare, C.; Longhi, R.; Heurteaux, C.; Vitadello, M.; Malgaroli, A. (2001-08-03). "Hyperpolarization-activated cyclic nucleotide-gated channel 1 is a molecular determinant of the cardiac pacemaker current I(f)". The Journal of Biological Chemistry. 276 (31): 29233–29241. doi:10.1074/jbc.M100830200. hdl:11577/1349322. ISSN 0021-9258. PMID 11328811.
  29. ^ a b DIFRANCESCO, D (May 2006). "Funny channels in the control of cardiac rhythm and mode of action of selective blockers". Pharmacological Research. 53 (5): 399–406. doi:10.1016/j.phrs.2006.03.006. ISSN 1043-6618. PMID 16638640.
  30. ^ Bucchi, Annalisa; Baruscotti, Mirko; DiFrancesco, Dario (2002-06-10). "Current-dependent Block of Rabbit Sino-Atrial Node If Channels by Ivabradine". Journal of General Physiology. 120 (1): 1–13. doi:10.1085/jgp.20028593. ISSN 1540-7748. PMC 2238187. PMID 12084770.
  31. ^ DiFrancesco, Jacopo C.; DiFrancesco, Dario (2015-03-10). "Dysfunctional HCN ion channels in neurological diseases". Frontiers in Cellular Neuroscience. 6: 174. doi:10.3389/fncel.2015.00071. ISSN 1662-5102. PMC 4354400. PMID 25805968.
  32. ^ Emery, Edward C.; Young, Gareth T.; Berrocoso, Esther M.; Chen, Lubin; McNaughton, Peter A. (2011-09-09). "HCN2 ion channels play a central role in inflammatory and neuropathic pain". Science. 333 (6048): 1462–1466. Bibcode:2011Sci...333.1462E. doi:10.1126/science.1206243. ISSN 1095-9203. PMID 21903816. S2CID 38379083.
  33. ^ Postea, Otilia; Biel, Martin (2011-11-18). "Exploring HCN channels as novel drug targets". Nature Reviews. Drug Discovery. 10 (12): 903–914. doi:10.1038/nrd3576. ISSN 1474-1784. PMID 22094868. S2CID 5586933.
  34. ^ Benzoni, Patrizia; Bertoli, Giorgia; Giannetti, Federica; Piantoni, Chiara; Milanesi, Raffaella; Pecchiari, Matteo; Barbuti, Andrea; Baruscotti, Mirko; Bucchi, Annalisa (November 2021). "The funny current: Even funnier than 40 years ago. Uncanonical expression and roles of HCN/f channels all over the body". Progress in Biophysics and Molecular Biology. 166: 189–204. doi:10.1016/j.pbiomolbio.2021.08.007. hdl:2434/863839. ISSN 1873-1732. PMID 34400215. S2CID 237147712.
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