Creating a Cardiac Pacemaker by Gene Therapy - Biopacemaking - page 48

Fig. 1. Top : diagram of the ionic mechanisms and membrane currents involved in the generation
and control of the pendulum of spontaneous electrical activity of the SAN cells. Reprinted from
Ref. 79, with permission. Bottom : representative tracings of ionic currents recorded in
spontaneously beating murine SAN cells. Reprinted from Ref. 60, with permission.
automaticity [26, 35, 36], I CaL is the main pacemaking current recorded at the center of
the SAN [7, 48]. Early on, it was described as a dihydropyridinesensitive [48, 80, 87]
current, activated at about -30 mV and responsive to catecholamines [41]. I CaT , too,
was proposed as a driver of the SAN diastolic depolarization [33, 41]. Described as a
high threshold current, typically sensitive to blockade by Ni 2+ , with activation in the
more hyperpolarized range (-50 mV), I CaT appeared to be lacking sensitivity to both
catecholamines and calcium channel blockers.
We now know that the different types of calcium channels are largely defined by
their respective pore forming Į 1 subunit, of which ten have been catalogued to date by
means of homology screening. They are grouped in three related families (Ca v 1, Ca v 2,
and Ca v 3) [25], whose function has been thoroughly characterized [38]. Ca v 1.2 and
Ca v 1.3 underlie the cardiac I CaL [38, 58, 61], with the latter having a particularly lower
activation threshold, slower inactivation, and lower sensitivity to dihydropyridines
than the former. Following findings, by Platzer et al. [70], that Ca v 1.3 knockout mice
had significantly altered SAN function, further work by others suggested that Ca v 1.3
is particularly important in the genesis of the pacemaker current in the SAN and in the
AVN [33, 59, 63, 91]. Also, indirect evidence is pointing to Ca v 1.3 as the subunit
responsible for cathecholaminergic sensitivity of I CaL [63] Altogether, these data
establish Ca v 1.3, distinct from other Ca v 1 subfamilies, as the ''pacemaker'' form of
I CaL [60] which is responsible for the control of contraction and possibly for the
upstroke phase of the action potential [59, 63].
Classically, and perhaps, at times, dogmatically, cardiac pacemaking has been
described as an exclusively membrane delimited mechanism. Speaking to a higher
degree of complexity of the natural pacemaker is an increasing evidence on the role
the so-called ''sarcoplasmic reticulum Ca 2+ clock'' (local calcium release, LCR, and
spontaneous calciumreleaseignited excitation , SCaRIE) [11, 57]. A novel