University: Università degli Studi di Milano, Italy

Main contributions:

• study physiological pacemaker mechanisms and role of HCN channels.
• generate a biological pacemaker.
• characterize human cardiac channelopathies linked to HCN.

Lab web-page: http://users.unimi.it/house2/HOME.htm

Contact: dario.difrancesco@unimi.it

Lay Summary:

Cardiac rhythmic activity is generated by "pacemaker" cells, which in mammals are located in the sino-atrial node (SAN). Action potentials of SAN cells have a special phase, called diastolic (or pacemaker) depolarization: at the end of an action potential, the membrane voltage slowly depolarizes until it reaches threshold for firing of a new action potential, thus generating repetitive activity.

In the last 3 decades we have investigated in detail the physiology of cardiac pacemaker mechanisms and the role of the If current in diastolic depolarization, characterizing its properties and function in generation of spontaneous activity and control of heart rate.

Substantial progress in the molecular understanding of pacemaking has been obtained with the cloning in the late 90s of the genes responsible for the If current, the HCN (Hyperpolarization-activated, Cyclic-Nucleotide-gated) channels. The major contribution of our group to the normaCOR project includes:

1) investigation of specific cellular localization of pacemaker HCN channels and their interaction with cellular micro-environments. Results will help clarify the mechanisms regulating HCN channels and pacemaking functions and will be helpful for the aims outlined below;

2) generation of a substrate for a "biological pacemaker" based on stem cells driven to differentiate to cardiac cells with autorhythmic properties similar to native pacemaker cells. The ultimate goal of this project will be to use biological pacemakers instead of the electronic devices implanted today in the therapy of various cardiac arrhythmias;

3) identification of mutations of human HCN (pacemaker) genes that cause cardiac pathologies affecting normal rhythm;

4) identification of the aminoacidic residues involved in the binding of ivabradine, a specific heart rate reducing agent, to specific HCN isoforms (such as HCN4, HCN1). The results will provide information critical to the understanding of the molecular HCN-drug interaction and will be useful for designing new, isoform-selective drugs.

Relevant Publications:

• Galvez BG, Sampaolesi M, Barbuti A, Crespi A, Covarello D, Brunelli S, Dellavalle A, Crippa S, Balconi G, Cuccovillo I, Molla F, Staszewsky L, Latini R, DiFrancesco D, Cossu G. Cardiac mesoangioblasts are committed, self-renewable progenitors, associated with small vessels of juvenile mouse ventricles. Cell Death Differ 2008/Sep; 15(9):1417-1428. 
• Barbuti A, Crespi A, Capilupo D, Mazzocchi N, Baruscotti M, DiFrancesco D. Molecular composition and functional properties of f-channels in murine embryonic stem cell-derived pacemaker cells. J Mol Cell Cardiol 2009/Mar; 46(3):343-351. 
• Lakatta EG, DiFrancesco D. What keeps us ticking: a funny current, a calcium clock, or both?. J Mol Cell Cardiol 2009/Aug 47(2):157-170. 
• Brioschi C, Dobrzynski H, Terragni B, Tellez J, Psioni G, Longhi R, Moroni P, Billeter R, Baruscotti M, Boyett MR & DiFrancesco. Distribution of the pacemaker HCN4 channel protein in the rabbit sinoatrial node. J Mol Cell Cardiol 2009/Aug; 47(2):221-227. 
• Baruscotti M, Barbuti A, Bucchi A. The cardiac pacemaker current. J Mol Cell Cardiol 2009/xxx:xx-xx. 
• Bucchi A, Barbuti A, Baruscotti M, DiFrancesco D. Heart rate reduction via selective 'funny' channel blockers. Curr Opin Pharmacol 2007/7(2):208-213. 
• Barbuti A, Baruscotti M, DiFrancesco D. The pacemaker current: from basics to the clinics. 2007 2007/18 (3):342-347. 
• Bucchi A, Baruscotti M, Robinson RB, Difrancesco D. Modulation of rate by autonomic agonists in SAN cells involves changes in. J Mol Cell Cardiol 2007/43 (1):39-48. 
• Barbuti A, Terragni B, Brioschi C & DiFrancesco D. Localization of f-channels to caveolae mediates specific beta2-adrenergic. J Mol Cell Cardiol 2007/42 :71-78. 
• Barbuti A & DiFrancesco D. Control Of Cardiac Rate by 'Funny' Channels In Health And Disease. Ann NY Acad Sci 2007/11123:213-23. 
• Bucchi A, Tognati A, Milanesi R, Baruscotti M & DiFrancesco D. Properties of ivabradine-induced block of HCN1 and HCN4 channels. Journal of Physiology 2006/572:335-346.  (Link)
• DiFrancesco D. Funny channels in the control of cardiac rhythm and mode of action of selective. Pharmacol Res 2006/53(5):399-406. 
• Milanesi R, Baruscotti M, Gnecchi-Ruscone T, DiFrancesco D. Familial sinus bradycardia associated with a mutation in the cardiac pacemaker. N Engl J Med 2006/354(2):151-157. 
• Altomare C, Bescond J, Tognati A, Ferroni A & Baruscotti M. Direct inhibition of the pacemaker (If) current in rabbit sinoatrial node cells by genistein. British Journal of Pharmacology 2006/147:36–44.  (Link)