Ion Channel Portrait of the Human Sinus Node

The sinoatrial node (SAN) initiates the heartbeat and the controls rate and rhythm of contraction. Extensive work in small mammals provided important information about the ionic mechanisms responsible for the generation of the unique action potential shape of the SAN and its spontaneous pacemaker activity.1 Despite great progress in understanding SAN function, the mechanisms underlying pacemaking in humans are incompletely understood.Article p 1562 The SAN is specifically equipped for its role as the primary pacemaker. The rhythmic action potentials are preceded by slow diastolic depolarization (DD), which brings the membrane potential to the threshold needed for excitation.1 Extensive connective tissue insulates the SAN from the right atrium and prevents interference of the negative atrial (resting) membrane potential with pacemaking.1 DD and SAN automaticity are driven by a complex interaction between different voltage-gated ion currents exclusively residing in the surface membrane of the SAN cells (membrane clock hypothesis). According to this hypothesis, the kinetics of channel activation and inactivation control the timing mechanisms of the currents that comprise the membrane clock.2,3 The slope of early DD is determined by the hyperpolarization-activated cyclic nucleotide-gated inward current If (or funny current), whereas late DD involves contribution of high-voltage activated L-type Ca2+ currents (ICa,L) and, to a lesser extent, low-voltage activated T-type Ca2+ currents (ICa,T). Mutations in the pore-forming Nav1.5 sodium channel subunit have been linked to bradycardia in humans.1 However, cardiac sodium channels are expressed in the peripheral region of the SAN only and their precise role in pacemaking is not fully understood.4The membrane clock hypothesis of pacemaking is well established, but recent findings by Dr Lakatta and colleagues have challenged the dominant role of the membrane clock mechanism.5,6 They provided evidence that local subsarcolemmal Ca2+ …