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]

Contents

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

Biography

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

Publications

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

Related Research Articles

<span class="mw-page-title-main">Artificial cardiac pacemaker</span> Medical device

An artificial cardiac pacemaker is a medical device, nowadays always implanted, that generates electrical pulses delivered by electrodes to one or more of the chambers of the heart, the upper atria or lower ventricles. Each pulse causes the targeted chamber(s) to contract and pump blood, thus regulating the function of the electrical conduction system of the heart.

<span class="mw-page-title-main">Refractory period (physiology)</span> Period of time after an organism performs an action before it is possible to perform again

Refractoriness is the fundamental property of any object of autowave nature not responding to stimuli, if the object stays in the specific refractory state. In common sense, refractory period is the characteristic recovery time, a period that is associated with the motion of the image point on the left branch of the isocline .

<span class="mw-page-title-main">Sinoatrial node</span> Group of cells located in the wall of the right atrium of the heart

The sinoatrial node is an oval shaped region of special cardiac muscle in the upper back wall of the right atrium made up of cells known as pacemaker cells. The sinus node is approximately 15 mm long, 3 mm wide, and 1 mm thick, located directly below and to the side of the superior vena cava.

<span class="mw-page-title-main">Pacemaker potential</span>

In the pacemaking cells of the heart (e.g., the sinoatrial node), the pacemaker potential (also called the pacemaker current) is the slow, positive increase in voltage across the cell's membrane (the membrane potential) that occurs between the end of one action potential and the beginning of the next action potential. This increase in membrane potential is what causes the cell membrane, which typically maintains a resting membrane potential around -65 mV, to reach the threshold potential and consequently fire the next action potential; thus, the pacemaker potential is what drives the self-generated rhythmic firing (automaticity) of pacemaker cells, and the rate of change (i.e., the slope) of the pacemaker potential is what determines the timing of the next action potential and thus the intrinsic firing rate of the cell. In a healthy sinoatrial node (SAN, a complex tissue within the right atrium containing pacemaker cells that normally determine the intrinsic firing rate for the entire heart), the pacemaker potential is the main determinant of the heart rate. Because the pacemaker potential represents the non-contracting time between heart beats (diastole), it is also called the diastolic depolarization. The amount of net inward current required to move the cell membrane potential during the pacemaker phase is extremely small, in the order of few pAs, but this net flux arises from time to time changing contribution of several currents that flow with different voltage and time dependence. Evidence in support of the active presence of K+, Ca2+, Na+ channels and Na+/K+ exchanger during the pacemaker phase have been variously reported in the literature, but several indications point to the “funny”(If) current as one of the most important.(see funny current). There is now substantial evidence that also sarcoplasmic reticulum (SR) Ca2+-transients participate to the generation of the diastolic depolarization via a process involving the Na–Ca exchanger.

<span class="mw-page-title-main">Cardiac conduction system</span> Aspect of heart function

The cardiac conduction system transmits the signals generated by the sinoatrial node – the heart's pacemaker, to cause the heart muscle to contract, and pump blood through the body's circulatory system. The pacemaking signal travels through the right atrium to the atrioventricular node, along the bundle of His, and through the bundle branches to Purkinje fibers in the walls of the ventricles. The Purkinje fibers transmit the signals more rapidly to stimulate contraction of the ventricles.

<span class="mw-page-title-main">Cardiac action potential</span> Biological process in the heart

The cardiac action potential is a brief change in voltage across the cell membrane of heart cells. This is caused by the movement of charged atoms between the inside and outside of the cell, through proteins called ion channels. The cardiac action potential differs from action potentials found in other types of electrically excitable cells, such as nerves. Action potentials also vary within the heart; this is due to the presence of different ion channels in different cells.

<span class="mw-page-title-main">Cyclic nucleotide–gated ion channel</span> Family of transport proteins

Cyclic nucleotide–gated ion channels or CNG channels are ion channels that function in response to the binding of cyclic nucleotides. CNG channels are nonselective cation channels that are found in the membranes of various tissue and cell types, and are significant in sensory transduction as well as cellular development. Their function can be the result of a combination of the binding of cyclic nucleotides and either a depolarization or a hyperpolarization event. Initially discovered in the cells that make up the retina of the eye, CNG channels have been found in many different cell types across both the animal and the plant kingdoms. CNG channels have a very complex structure with various subunits and domains that play a critical role in their function. CNG channels are significant in the function of various sensory pathways including vision and olfaction, as well as in other key cellular functions such as hormone release and chemotaxis. CNG channels have also been found to exist in prokaryotes, including many spirochaeta, though their precise role in bacterial physiology remains unknown.

Chronotropic effects are those that change the heart rate.

<span class="mw-page-title-main">T-tubule</span> Extensions in cell membrane of muscle fibres

T-tubules are extensions of the cell membrane that penetrate into the center of skeletal and cardiac muscle cells. With membranes that contain large concentrations of ion channels, transporters, and pumps, T-tubules permit rapid transmission of the action potential into the cell, and also play an important role in regulating cellular calcium concentration.

Adenosine A<sub>1</sub> receptor Cell surface receptor found in humans

The adenosine A1 receptor (A1AR) is one member of the adenosine receptor group of G protein-coupled receptors with adenosine as endogenous ligand.

<span class="mw-page-title-main">Ivabradine</span> Heart medication

Ivabradine, sold under the brand name Procoralan among others, is a medication, which is a pacemaker current (If) inhibitor, used for the symptomatic management of heart-related chest pain and heart failure. Patients who qualify for use of Ivabradine for coronary heart failure are patients who have symptomatic heart failure, with reduced ejection volume, and heart rate at least 70 bpm, and the condition not able to be fully managed by beta blockers.

<span class="mw-page-title-main">Denis Noble</span> British biologist

Denis Noble is a British physiologist and biologist who held the Burdon Sanderson Chair of Cardiovascular Physiology at the University of Oxford from 1984 to 2004 and was appointed Professor Emeritus and co-Director of Computational Physiology. He is one of the pioneers of systems biology and developed the first viable mathematical model of the working heart in 1960. Noble established The Third Way of Evolution (TWE) project with James A. Shapiro which predicts that the entire framework of the modern synthesis will be replaced.

The pacemaker current is an electric current in the heart that flows through the HCN channel or pacemaker channel. Such channels are important parts of the electrical conduction system of the heart and form a component of the natural pacemaker.

A biological pacemaker is one or more types of cellular components that, when "implanted or injected into certain regions of the heart," produce specific electrical stimuli that mimic that of the body's natural pacemaker cells. Biological pacemakers are indicated for issues such as heart block, slow heart rate, and asynchronous heart ventricle contractions.

<span class="mw-page-title-main">Afterhyperpolarization</span>

Afterhyperpolarization, or AHP, is the hyperpolarizing phase of a neuron's action potential where the cell's membrane potential falls below the normal resting potential. This is also commonly referred to as an action potential's undershoot phase. AHPs have been segregated into "fast", "medium", and "slow" components that appear to have distinct ionic mechanisms and durations. While fast and medium AHPs can be generated by single action potentials, slow AHPs generally develop only during trains of multiple action potentials.

<span class="mw-page-title-main">HCN2</span> Protein-coding gene in the species Homo sapiens

Potassium/sodium hyperpolarization-activated cyclic nucleotide-gated ion channel 2 is a protein that in humans is encoded by the HCN2 gene.

<span class="mw-page-title-main">HCN4</span> Protein-coding gene in the species Homo sapiens

Potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 4 is a protein that in humans is encoded by the HCN4 gene.

<span class="mw-page-title-main">HCN1</span> Protein-coding gene in the species Homo sapiens

Potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 1 is a protein that in humans is encoded by the HCN1 gene.

Hyperpolarization-activated cyclic nucleotide–gated (HCN) channels are integral membrane proteins that serve as nonselective voltage-gated cation channels in the plasma membranes of heart and brain cells. HCN channels are sometimes referred to as pacemaker channels because they help to generate rhythmic activity within groups of heart and brain cells. HCN channels are activated by membrane hyperpolarization, are permeable to Na + and K +, and are constitutively open at voltages near the resting membrane potential. HCN channels are encoded by four genes and are widely expressed throughout the heart and the central nervous system.

<span class="mw-page-title-main">Medial septal nucleus</span>

The medial septal nucleus (MS) is one of the septal nuclei. Neurons in this nucleus give rise to the bulk of efferents from the septal nuclei. A major projection from the medial septal nucleus terminates in the hippocampal formation.

References

  1. ↑ "Dario DiFrancesco: Curriculum vitae" (PDF).
  2. 1 2 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. 1 2 3 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. 1 2 3 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. 1 2 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. 1 2 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. 1 2 "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. 1 2 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.
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  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. 1 2 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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  40. 1 2 "IUPS Academy of Physiology". International Union of Physiological Sciences. Retrieved 2022-07-01.
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