The activation of the funny current (if) in cardiac SAnode cells, which is gated by cyclic nucleotides and designated HCN, is triggered by hyperpolarization. The HCN gene family consists of four members and these channels are found in neurons of the central nervous system that repetitively generate action potentials. The voltage sensors, which are present in voltage-gated sodium, potassium, and calcium channels, are also found in transmembrane segment 4 (S4) of HCN. The dominant channel expressed in the heart is derived from the HCN4 gene. Mutations in the amino acids of S4 and the S4-to-S5 linker cause significant changes in the voltage dependence of activation, requiring greater hyperpolarization to open the channel. This effect is similar to that of acetylcholine and it is predicted that such mutations in the human heart could underlie sinus bradycardia and sick sinus syndrome.

Fig. 16.20 illustrates the membrane action potentials recorded from a sino-atrial node pacemaker cell. The addition of calcium channel antagonists or the reduction in the concentration of Ca++ in the bath diminishes the amplitude of the action potential and the slope of the slow diastolic depolarization in SA node cells. Research evidence suggests that other ion currents, including a sustained inward Na+ current (iNa), the T-type Ca++ current, and the Na+/Ca++ exchange current triggered by spontaneous release of Ca++ from the sarcoplasmic reticulum, may also be involved in pacemaking. These observations highlight the various ways in which this vital function can be sustained.

In special circumstances, regions of the heart other than the SAnode may initiate beats. These sites are known as ectopic foci or ectopic pacemakers. Ectopic foci can become pacemakers when their own rhythmicity is enhanced, the rhythmicity of higher order pacemakers is depressed, or all conduction pathways between the ectopic focus and regions with greater rhythmicity become blocked. Ectopic pacemakers can act as a safety mechanism when normal pacemaking centers fail. However, if an ectopic center fires while the normal pacemaking center is still functioning, the ectopic activity may induce sporadic rhythm disturbances, such as premature depolarizations, or continuous rhythm disturbances, such as paroxysmal tachycardias.

The autonomic neurotransmitters have an impact on automaticity by modifying membrane ionic currents. Adrenergic transmitters increase all three currents involved in SA nodal automaticity. To increase the slope of diastolic depolarization, the enhancement of if and iCa by adrenergic transmitters must exceed the augmentation of iK by these same transmitters.

Acetylcholine released from vagus nerve endings in the heart induces hyperpolarization through the activation of specific potassium channels, known as a. The ionic basis for automaticity in AV node pacemaker cells is similar to that in SA node cells. Similar mechanisms also account for automaticity in ventricular Purkinje fibers, except that the fast Na+ current, rather than iCa, is involved. Additionally, it has been suggested that a voltage- and time-dependent K+ current, rather than the hyperpolarization-induced inward current if, mediates the slow diastolic depolarization; however, this still needs to be clarified.
Theso-calledfunnycurrent(if)incardiacSAnodecellsisactivatedbyhyperpolarizationandgatedbycyclicnucleotides,anditschannelisdesignatedHCN.TherearefourmembersoftheHCN genefamily,andsuchchannelsarefoundincentralnervoussystemneuronsthatgenerateactionpotentialsrepetitively.Transmembranesegment4(S4)ofHCNhasmanypositivelychargedaminoacidsthatactasvoltagesensors,whicharealsopresentinvoltage-gatedsodium,potassium,andcalciumchannels.ThedominantchannelexpressedintheheartisderivedfromtheHCN4 gene.MutationsinaminoacidsinS4andintheS4-to-S5linkercausemarkedchangesinthevoltagedependenceofactivation,insuchawaythatgreaterhyperpolarizationisneededtoopenthechannel.Thiseffectislikethatofacetylcholine,andithasbeenpredictedthattheoccurrenceofsuchmutationsinthehumanheartcouldunderliesinusbradycardiaandsicksinussyndrome.
•Fig. 16.20 Membrane Action Potentials Recorded From an Sino-atrial Node Pacemaker Cell. TheconcentrationofCa++inthebathwasreducedfrom2to0.2mmol/L(“mM”).(ModifiedfromKohlhardtM,etal.Basic Res Cardiol. 1976;71:17.)–60 0 Ca++ 2 mM 500 msec Ca++ 0.2 mM mV
Fig. 16.20 ) or the addition of calcium channel antagonists diminishes the amplitude of the action potential and the slope of the slow diastolic depolarization in SA node cells. Research evidence indicates that additional ion currents—including a sustained (background) inward Na+ current (iNa), the T-type Ca++ current, and the Na+/Ca++ exchange current triggered by spontaneous release of Ca++ from the sarcoplasmic reticulum—may also be involved in pacemaking. These observations illustrate the many ways to sustain this vital function.
RegionsoftheheartotherthantheSAnodemayinitiatebeatsinspecialcircumstances.Suchsitesarecalledectopic foci orectopic pacemakers. Ectopicfocimaybecomepacemakerswhen(1)theirownrhythmicitybecomesenhanced,(2)therhythmicityofthehigherorderpacemakersbecomesdepressed,or(3)allconductionpathwaysbetweentheectopicfocusandregionswithgreaterrhythmicitybecomeblocked.Ectopicpacemakersmayactasasafetymechanismwhennormalpacemakingcentersfail.However,ifanectopiccenterfireswhilethenormalpacemakingcenterstillfunctions,theectopicactivitymayinduceeithersporadicrhythmdisturbances,suchasprematuredepolarizations,orcontinuousrhythmdisturbances,suchasparoxysmaltachycardias(seethesection“
The autonomic neurotransmitters affect automaticity by altering membrane ionic currents. The adrenergic transmitters increase all three currents involved in SA nodal automaticity. To increase the slope of diastolic depolarization, the augmentation of if and iCa by adrenergic transmitters must exceed the enhancement of iK by these same transmitters.
The hyperpolarization induced by acetylcholine released from vagus nerve endings in the heart is achieved by the activation of specific potassium channels: the aThe ionic basis for automaticity in AV node pacemaker cells resembles that in SA node cells. Similar mechanisms also account for automaticity in ventricular Purkinje fibers, except that the fast Na+ current rather than iCa is involved. Also, a voltageand time-dependent K+ current rather than the hyperpolarization-induced inward current if has been suggested to mediate the slow diastolic depolarization; however, this remains to be clarified.