par- 12 mars
Canaux ioniques et activité pace-maker cardiaque.
Cardioprotection contre les lésions d’ischémie-reperfusion
Genetics and Physiology of the heart automaticity
By commencing the contraction of the working myocardium, heart automaticity ensures the correct time setting of the blood flow into vessels, thereby playing a key role in integration of vital functions of the organism. The automaticity of the heartbeat has fascinated scientists, philosophers and even artists well before the establishment of the foundations of the modern science. The persistency of the heart beating outside the body is in fact, a naturally intriguing and fascinating observation. In the medical practice, the presence or absence of the heartbeat has established the boundary between life and death for centuries. Even at the present days, the link between the heartbeat and our intimate concept of life is powerful and still constitutes one important issue in the setting of standards for the clinical and ethical definition of death. Beside the doubtless fascination exerted by the heartbeat, the study of the mechanisms underlying cardiac pacemaker activity is a challenging and demanding research field in the modern Physiology. The ionic basis of cardiac pacemaking have been investigated since the end of the sixties by applying the double-electrode voltage-clamp technique on strips of spontaneously active tissue coming from the Purkinje fibers network and the sino-atrial node (SAN). During this pioneering research period, the principles of functioning of the pacemaker action potential and some of ionic currents potentially involved in the generation of automaticity have been described.
We described the functional roles for L-type Cav1.3 and T-type Cav3.1 Ca2+ channels in cardiac automaticity and impulse conduction of mice and humans and showed that loss-of-function of Cav1.3 channels underlies congenital bradycardia and conduction defects. We thus developed a unique collection of mouse models of human disease of automaticity based on Cav1.3, hyperpolarization-activated (HCN) and Cav3.1 channel dysfunction. Our group will follow two main objectives :
to unravel the mechanisms by which Cav1.3 channels contribute to the generation and regulation of pacemaking by the autonomic nervous system and indicate possible therapeutic strategies to rescue Cav1.3 loss-of-function. Our preliminary data indicate that Cav1.3 channels contribute to pacemaking by both driving inward current in the diastolic depolarization and by functional crosstalk with ryanodine receptors and that it is possible to rescue Cav1.3 loss-of-function by genetic or pharmacological inactivation of IKACh channels (GIRK4), without altering the absolute capability of the animal to regulate its heart rate. We will thus study rescuing of Cav1.3-/- phenotype in depth and screen potential drug candidates to antagonize GIRK4 channel activity.
to study the phenotype of Cav1.3-/- crossed with different strains in which ion channels involved in the generation of pacemaker activity have been inactivated or modified (Cav3.1, GIRK4 and dominant-negative HCN isoforms). All these strains are already available in our collection. This approach will allow us to further elucidate the mechanisms underlying cardiac automaticity and its regulation by the autonomic nervous system.
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