Normal excitation of the heart
Cardiac electrical activity starts by the spontaneous excitation of “pacemaker” cells in the sinoatrial node in the right atrium. Pacemaker automaticity is due to spontaneous diastolic repolarization of phase 4 that generates rhythmic action potentials and determines the heart rate through various currents, including the If current. There are no histologically specialized conduction tissues between the sinus and AV node, and the sinus impulse is transmitted via several exit pathways which electrically bridge the nodal tissue and atrial myocardium, and then preferentially toward the AV node via muscle bundles with well aligned arrangement of cardiomyocytes. By traveling through intercellular gap junctions (cell-to-cell connections), the excitation wave depolarizes adjacent atrial myocytes, ultimately resulting in excitation of the atria. The excitation wave then propagates via the atrioventricular node and the Purkinje fibers to the ventricles, where ventricular myocytes are depolarized, resulting in excitation of the ventricles. Depolarization of each atrial or ventricular myocyte is represented by the initial action potential (AP) upstroke (phase 0), where the negative resting membrane potential (approximately −85 mV) depolarizes to positive voltages ( Figs. 2.1 and 2.2 and Table 2.1 ). The action potential is produced by transmembrane flow of ions (inward depolarizing currents mainly through Na + and Ca 2+ channels, and outward repolarizing currents mainly through K + channels). , The resting potential of atrial and ventricular myocytes during AP phase 4 (resting phase) is stable and negative (–85 mV) because of the high conductance of the potassium channels. Excitation by electrical impulses from adjacent cells activates the inward Na + current that depolarizes myocytes rapidly (phase 0). Transient outward K + current (phase 1) creates a notch during the early phase of repolarization (I to ). Balance of the inward depolarizing L-type Ca 2+ current (I Ca-L ) and outward rectifier K + currents (slow I Ks , rapid I Kr , and ultra-rapid I Kur ) forms a plateau phase (phase 2). Deactivation (closing) of the inward current I Ca-L and increase of the outward currents creates phase 3 with final repolarization mainly because of potassium efflux through the inward rectifier I K1 channels, and the membrane potential returns to its resting potential (phase 4). The pacemaker current (I f ) contributes to action potential generation in the sinus node and significantly determines heart rate. I f is an inward current activated on hyperpolarization. It is called the funny current because despite being an inward current, it behaves like a pure K + current (as a result of superimposition of I k1 ). In Purkinje fibers, a similar behavior is expressed by current I k2 . I f activation is accelerated by intracellular cyclic adenosine monophosphate (cAMP) levels and thus regulated by sympathetic and parasympathetic activity, which controls synthesis and degradation of intracellular cAMP, respectively.
| CURRENT/SYMBOL | PROTEIN | GENE | VENTRICLE | ATRIUM |
|---|---|---|---|---|
| Voltage-Gated Inward Currents | ||||
| Fast Na + current, I Na | Nav1.5 | SCN5A | +++ | +++ |
| L-type Ca 2 + current, I CaL (dihydropyridine receptor: DHPR) | Ca v 1.2 | CACNA1C | +++ | ++ |
| Voltage-Gated Outward Currents | ||||
| Fast transient outward K + current, I to,f | Kv4.2 | KCND2 | ++ | +++ |
| Kv4.3 | KCND3 | |||
| Slow transient outward K + current, I to,s | KV1.4 | KCNA4 | ++ | +++ |
| Delayed rectifier K + current, I Kr | Kv11.1 | KCNH2 (HERG) | +++ | + |
| Delayed rectifier K + current, I Ks | Kv7.1 | KCNQ1 | +++ | + |
| 4-Aminopyridine-sensitive, rapidly activating, slowly inactivating K + current, I Kslow1 | Kv1.5 | KCNA5 | − | − |
| 4-Aminopyridine-insensitive, rapidly activating, slowly inactivating K + current, I Kslow2 | Kv2.1 | KCNB1 | − | − |
| Sustained 4-aminopyride-sensitive ultrarapid delayed rectifier K + current, I Kur | Kv1.5 | KCNA5 | − | ++ |
| Inward Rectifiers | ||||
| Inwardly rectifying current I K1 | Kir2.1 | KCNJ2 | +++ | ++ |
| Kir2.2 | KCNJ12 | |||
| Acetylcholine-activated, K + current, I KACh | Kir3.1 | KCNJ3 | − | +++ |
| Kir3.4, | KCNJ5 | |||
| ATP-sensitive potassium channel, I K2 p | Kir6.2 | KCNJ11 | ++ | ++ |
| Leak Currents | ||||
| Two-pore domain K + leak current, I K2 p | K2p3.1 | KCNK3 | +++ | ++ |
| Ca 2+ -activated K + current, I KCa | KC a 2.x- | KCNNx | − | +++ |
| Exchange Currents | ||||
| Transient, inward, Na + -Ca 2+ exchange current, I ti | NCX | SLC8A1 | ++ | ++ |
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