The magnitude of ito during the plateau is greater in atrial myocytes than in ventricular myocytes. The duration of the action potential in ventricular myocytes varies depending on their location in the ventricular walls. The i to and iK currents are mainly responsible for these differences. In endocardial myocytes, which have the shortest action potential duration, the magnitude of iK is the highest. The opposite is true for midmyocardial myocytes. Epicardial myocytes have intermediate values for both iK magnitude and action potential duration.
The iK1 current does not contribute to repolarization initiation because its channels have very small conductance during the plateau phase. However, the iK1 channels play a significant role in accelerating repolarization once phase 3 has been initiated. As the membrane voltage becomes more negative during phase 3, the conductance of iK1 channels increases, leading to faster repolarization.
During phase 4, the steady inward leak of Na+ is counteracted by the Na+,K+-ATPase, preventing the resting membrane voltage from depolarizing. Excess Ca++ ions that entered the cell during phase 2 are eliminated mainly by a 3Na+-Ca++ antiporter, which exchanges three Na+ ions for one Ca++ ion. Some Ca++ ions are also removed by an ATP-driven Ca++ pump.
Ion channels in cardiomyocytes form macromolecular complexes with cellular proteins. These complexes are involved in modulating the transport, localization, operation, post-translational modification, and turnover of specific ion channels. The carboxyterminals of ion channels connect them to intracellular proteins such as PDZ domain proteins, which interact with synapse-associated protein (SAP97), syntrophin, and A-kinase anchoring protein (AKAP5). Different macromolecular complexes are found in distinct cellular locations, contributing to ion channel distribution. The voltage-sensitive sodium channel (Nav1.5) is linked to syntrophin/dystrophin at lateral cell membranes and to ankyrinB, plakophilin-2, and calmodulin-dependent protein kinase II at the intercalated disk. Different ion channels can be connected within the same complex, or channelosome, with SAP97. This connection not only affects their localization but also allows changes in the abundance of Kir2.1 channels to influence Nav1.5 abundance, and vice versa. Therefore, the complex containing Kir2.1 and Nav1.5 channels has a significant impact on excitability and its regulation under normal and pathological conditions, including arrhythmias.
Fig. 16.10 ) because the magnitude •Fig. 16.10 Typical Action Potentials (in Millivolts, y-Axis). Thesepotentialswererecordedfromcellsintheventricle(A), sinoatrial(SA)node(B), andatrium(C). NotethatthetimecalibrationinB differsfromthatinA andC. Numbersonthecurvesdenotethephasesoftheactionpotential.(FromHoffmanBF,CranefieldPF.Electrophysiology of the Heart. NewYork:McGraw-Hill;1960.) of ito during the plateau is greater in atrial myocites than in ventricular myocytes. As already noted, the duration of the action potential in ventricular myocytes varies considerably with the location of these myocytes in the ventricular walls (see
Fig. 16.5). The i to and iK currents mainly account for these differences. In endocardial myocytes, in which the duration of the action potential is least, the magnitude of iK is greatest. The converse applies to the midmyocardial myocytes. The magnitude of iK and the duration of the action potential are intermediate for epicardial myocytes.
The iK1 current does not participate in the initiation of repolarization because the conductance of these channels is very small over the range of Vm values that prevail during the plateau. However, the iK1 channels contribute substantially to the rate of repolarization once phase 3 has been initiated. As Vm becomes increasingly negative during phase 3, the conductance of the channels that carry the iK1 current progressively increases and thereby accelerates repolarization (see
Fig. 16.3
Restoration of Ionic Concentrations (Phase 4)
The steady inward leak of Na+ that enters the cell rapidly during phase 0 and more slowly throughout the cardiac cycle would gradually depolarize the resting membrane voltage were it not for Na+,K+-ATPase, which is located in the cell membrane (see ). Similarly, most of the excess Ca++ ions that had entered the cell mainly during phase 2 are eliminated principally by a 3Na+-Ca++ antiporter, which exchanges three Na+ ions for one Ca++ ion. However, some of the Ca++ ions are eliminated by an ATP-driven Ca++ pump.
Cardiacionchannelsareconnectedtocellularproteinstoformmacromolecularcomplexes.Thesecomplexesareinvolvedinmodulatingthetransport,membranelocalization,operation,posttranslationalmodificationandturnoverofparticularionchannels.ThecarboxyterminalsofionchannelslinkthemwithseveralintracellularproteinssuchasPDZ(postsynapticdensity,disclarge,andzonulaoccludens-1)domainproteinswhosebindingsitesinteractwithsynapse-associatedprotein(SAP97),syntrophin,andA-kinaseanchoringprotein(AKAP5)amongothers.Differentmacromolecularcomplexesarefoundindistinctcellularlocations,andthisisthoughttounderlieionchanneldistribution.Thevoltage-sensitivesodiumchannel(Nav1.5)islinkedwithsyntrophin/dystrophinatlateralcellmembranesandwithankyrinB,plakophilin-2,andcalmodulin-dependentproteinkinaseIIattheintercalateddisk.Also,differentionchannelscanfoundinthesamecomplex.ThusNav1.5channelsandinward-rectifyingK(Kir2.1)channelscanbeconnectedinacomplex,orchannelosome, withSAP97.ThislinknotonlyaffectsthelocalizationbutalsoallowschangesintheabundanceofKir2.1channelstoproducereciprocalchangesinNav1.5abundance;theconverseisalsoobserved.ThusthecomplexcontainsKir2.1,whichsetstherestingmembranepotential,andNav1.5,whichaccountsforrapidexcitation.Colocalizationofthesetwochannelsthereforeexertsapowerfuleffectonexcitabilityanditsregulationundernormalandpathologicalconditions(arrhythmias).