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Cardiac AP Notes-2020 DeWayne Townsend PHSL 4702/5702 Cell Physiology Fall, 2020 Cardiac Action Potential Cardiac Conduction Voltage Gated Ca2+ Channels Anatomical Regions Structure and isoforms Pacemaking Cells Gating properties Role in Automaticity Anatomy of the Cardiac Action Potential Role in Contractile Muscle Diastolic Depolarization Important Currents Cardiac K+ Channels Transient Outward Current Hyperpolarization-Cyclic Nucleotide-Gated Delayed Rectifiers Channel G-Protein Linked Inward Rectifying K+ Channel Structure and isoforms ATP Activated K+ Channel GENESIS AND REGULATION OF THE HEART AUTOMATICITY 921 Gating properties Cardiac Cl- Channels Voltage Gated Na+ Channels Cardiac CFTRregulation of pacemaker activity have been obtained: the venosus (227, 228) and mammalian SAN (44) has been Structure and isoforms Rectifyingrelevance Cl- Channels of f-channels in the regulation of heart rate at recently highlighted, and the contribution of spontaneous 2 Gating properties Ca2+ Activatedlow parasympatheticCl- Channels tone (124) and the physiological intracellular Ca ϩ release in the generation of automatic- Role in Automaticity significance of the heterogeneity of ion channel expres- ity has been emphasized (510). Role in Contractile Muscle Connexins sion in the SAN (58). The importance of the Naϩ-Ca2ϩ New important insights into the pacemaker mecha- Structureexchanger and isoforms (NCX) in pacemaking in the amphibian sinus nism are now coming from the study of genetically mod- Gating properties ified mouse strains in which specific ion channels have been inactivated or modified. This genetic approach con- Cardiac Conduction stitutes a necessary implementation to electrophysiologi- cal and pharmacological evidence, since selective inhibi- Anatomical Regions tors of ion channels are not always available. Gene tar- In healthy hearts, the cardiac action geting in the mouse has generated interesting models of dysfunction of pacemaker activity (393, 467, 522). The potential originates in specialized possibility to study pacemaker activity in mouse models is Downloaded from pacemaking cells in the sinoatrial node (Fig. very recent (312, 313) and has provided exciting insights 1). This depolarization is spread from these into the specific functional role of L-type Cav1.3 (309, 546) pacemaker cells to the atrial cardiac and T-type Cav3.1 (314) channels in the generation of SAN myocytes. This depolarization reaches a automaticity. Because of the tiny size of the dominant group of cells at the border of the atria and pacemaker region in the mouse heart (498), isolation of mouse SAN cells is technically challenging. Our group has http://physrev.physiology.org/ ventricular chambers called the been the first to obtain recordings of automaticity and ion atrioventricular node. These cells have a channels from isolated mouse SAN cells (312, 313). Other slowed conduction time resulting in a delay groups have successfully employed this new preparation of transmission of the cardiac action to study pacemaker activity in wild-type (86, 93, 279) and potential from the atria to the ventricule. A genetically modified mouse strains (196, 294, 309, 314, Figure 1. Diagram of the cardiac conduction pathways. 546). Limitations of the use of the mouse for the study of SCV- superior vena cava, SAN- sinoatrial node, CFB- fibrous band at the level of mitral and cardiac automaticity are correlated with the very high tricuspid valves, prevents direct spreading central fibrous body, AVN- atrioventricular node, AVB- atrioventricular bundle, BB - bundle branch, PFN- Purkinje basal heart rate of this species. We can thus expect that of the action potential to the ventricular fiber network, ICV- inferior vena cava. From Mangoni et pacemaker mechanisms may assume a different role in by 10.220.33.5 on July 18, 2017 muscle. After passing through the AV-node, al., 2008. mice than in larger mammals and humans. Nevertheless, the depolarization enters the Purkinje fiber the new possibility of isolating mouse SAN tissue and primary pacemaker cells has created a new interest into network, which rapidly transmits the depolarization toward the apex of the heart. At this the study of the ionic basis of pacemaker activity gener- point the depolarization comes in contact with the contractile cells of the ventricle. This ation and regulation. arrangement results in the synchronized contraction of both the right and left ventricules Until the last decade, research on the physiology of from the apex toward the heart valves. Importantly, each of these cell types has a heart automaticity was limited to the domain of basic unique action potential signature that reflects the role of the action potential in each of science. However, there is currently a renewal of interest these cells along the conduction system (Fig. 2). on cardiac pacemaking, and an increasing number of laboratories are now focusing their efforts on the regula- tion of heart rate. Indeed, the pharmacological control of cardiac automaticity is now becoming an important issue in the management of ischemic heart diseases (123). Iden- FIG. 1. A: the mammalian heart with the cardiac conduction system. The sinoatrial node (SAN) is located at the entry of the superior vena cava (SCV) in the right atrium (RA). The atrioventricular node (AVN) extends in a region delimited by the inferior vena cava (ICV), the central fibrous body (CFB), and the tricuspid valve (TV). The atrioventricular bundle (AVB) divides in the bundle branches (BB) and originates the left and right Purkinje fibers network (PFN). Other abbreviations are: LA, left atrium; PV, pulmonary veins; MV, mitral valve; RV, right ventricle; LV, left ventricle. [Adapted from Moorman and Christoffels (341).] B: recordings of automaticity and action potential waveforms of isolated mouse SAN, AVN, and PFN cells. Cl, cycle length; APD, action potential duration; Eth, action potential threshold; LDD, linear part of the diastolic depolarization; EDD, exponential part of the diastolic depolarization. (From Marger Nargeot and Matteo Mangoni, unpublished observations.) Physiol Rev • VOL 88 • JULY 2008 • www.prv.org DeWayne Townsend PHSL 4702/5702 Cell Physiology Fall, 2020 Pacemaking Cells There are several cells within the heart capable of generating rhythmic action potentials. Each of these cells display diastolic depolarization, a steady increase in membrane potential following the hyperpolarization of proceeding action potential. These cells are highly concentrated in the sinoatrial (SA) and atrioventricular (AV) nodes, although the Purkinje fibers are also capable of diastolic depolarization. The cells in the SA node display the most rapid diastolic depolarization. Therefore, they are the first to reach the threshold potential for initiating an action potential and are Figure 2. Action potential tracings from different regions of the cardiac conduction system. Color coded to demonstrate which responsible for producing normal cardiac portions of the traveling depolarization is responsible for which action potentials. aspect of the surface ECG tracing. Anatomy of the Cardiac Action Potential In many respects the cardiac action potential is quite similar to those of other excitable tissues that have been previously discussed in this course. The following section will focus on several of the unique features of the cardiac action potential. Diastolic Depolarization One of the defining feature of the cardiac action potential is the periodicity of its initiation. This phenomenon is the result of the presence of a diastolic depolarization in specific cells that generate cardiac action potentials. These pacemaker cells are influenced by the inputs from the nervous system, especially both Figure 3. A generic cardiac action potential. Upper tracing measures branches of the autonomic nervous the membrane potential (y-axis) versus time (x-axis). Phase 4 occurs system. The depth of diastolic during diastole and is sloped in pacemaker cells (left side), but relatively hyperpolarization and the slope of flat in contracting myocardium (right side). Individual currents and their activation kinetics are shown in the lower portion of the figure. FUNCTION OF HCN CHANNELS 851 ϳ0.5% (440, 441). The functional relevance of Ca2ϩ entry 333, 341, 344, 400) but are missing in Caenorhabditis through Ih channels is not clear at the moment. It was elegans, yeast, and prokaryotes. assumed that in dorsal root ganglion neurons, Ca2ϩ influx In all mammals investigated so far, four homologous through Ih channels at negative potentials contributes to HCN channel subunits (HCN1-4) exist. HCN1-4 are also activity-evoked secretion (441). present in the genome of fishes (e.g., Tetraodon nigro- There is an ongoing controversy on the size of the viridis and Takifugu rubripes). Analysis of genomic se- DeWayne Townsend PHSL 4702/5702 Cell Physiology Fall, 2020 single-channel conductance of Ih. Originally, single-chan- quences suggests that HCN2–4 genes underwent duplica- nel conductance was found to be very low, in the range of tions in the fish lineage increasing the number of potential ϳ1 pS (110). This estimate is in good agreement with very HCN species (194). HCN homologs have also been cloned diastolicrecent data depolarization (210). However, are single-channel the chief conductances determinantsfrom of the several heart invertebrates rate. including arthropods [e.g., that are 10–30 times higher have been reported for cloned spiny lobster (157), insects (158, 211, 251)] and sea ur- ImportantHCN channels Currents (267) as in well the
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