• choosing a few hot targets, for which partners can prove internationally renowned experience
• privileging those targets where a sufficient level of functional integration can be reached, thus allowing us to shoot from description of elementary mechanisms (ion channels, intracellular pathways) to clinical applicable evidence.

To gain this result, eight partners from five different European countries are involved. The main contributions of the partners to the research and technological activities of this STREP are detailed on their individual pages (see left).

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.