CVPR 03-25-14 08-09am Cardiac Ion Channels & Action Potentials - Beam Flashcards Preview

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Flashcards in CVPR 03-25-14 08-09am Cardiac Ion Channels & Action Potentials - Beam Deck (68):

In the heart, electrical activity...

1. Generates repetitive firing in specialized "pacemaker" regions...... 2. Propagates w/in the myocardium and via specialized conductive pathways......3. Serves as a trigger for contraction of the myocardium.


Cardiac action potential trigger…

… increase in intracellular concentration of Ca2+ --> contraction of myocardium


Cardiac action potentials are initiated by…

…pacemaker cells, which slowly depolarize to threshold in the absence of extrinsic input.


Normally, heart rate is controlled by & modulated by …

… pacemaker cells in the SA node, which fire intrinsically at ~100/min.... Rate modulated by autonomic nervous system (slow to 60-80/min = parasympathetic tone)


SA node

a cluster of small, round & spindle-shaped cells that contain few myofilaments, that are spontaneously active (automaticity), and that will fire APs at a frequency of ~100/min (rhythmicity); innervated by both sympathetic & parasympathetic axons.


Parasympathetic innervations of SA node

Ongoing activity in parasympathetic axons (parasympathetic tone) typically slows the rate at which cells in the SA node fire to 60-80 action potentials/min.


Automaticity of SA node vs. Automaticity of other cells (AV, etc.)

Cells in AV node and other heart regions may have automaticity, but the frequency at which they would fire APs is lower (slower) than the frequency of discharge SA node cells….Consequently, the SA node dominantes the pacemaker frequency & the other cells are normally driven by the SA node's APs (overdrive suppression)


Ectopic pacemakers

Under abnormal circumstances cells outside of the SA node that have spontaneous activity (especially cells in damaged regions of the myocardium) can take over initiation of the heartbeat from the SA node


Coordination of contraction – what must occur

B/c heart rate is controlled by electrical activity of the SA node, the propagation of this activity to other regions of the heart has to occur such that the two atria contract and relax in a coordinated fashion, that two ventricles contract and relax in a coordinated fashion, and that ventricular contraction occurs during atrial relaxation (and vice versa).


Coordination of contraction - how

1. Gap junctions connecting individual myocytes provide for cell-to-cell propagation of action potentials w/in the atrial myocardium, as well as w/in the ventricular myocardium....... 2. Specialized conductive pathways, in which individual cells are also connected by gap junctions, conduct the AP from SA node to left atrium and to AV node.


Atrioventricular node (AV node)

A cluster of small cells located on the right side of the inter-atrial septum near the opening of the coronary sinus…. In normal heart, the only place where APs can spread from atria (SA node) to the ventricles; Elsewhere, myocardial cells in the atria are electrically insulated from those in the ventricles by an intervening layer of CT


Conducting from the AV node

Additional conducting pathways propagate the action potential to the left & right ventricles. Cells in these conducting pathways are relatively large in diameter, so that the APs propagate more rapidly through them than through typical myocardial cells (which are half the size)


Trigger for Contraction

In myocardium, AP lasts a few hundred ms & triggers a sustained contraction of about the same duration….APs in SA & AV nodes are somewhat briefer, but still much longer than the APs in skeletal muscle (only last ~1 ms)


Sodium current (INa)

Cardiac sodium channels (containing NaV1.5 as the principle subunit) are similar to sodium channels in neurons and skeletal muscle…..Depolarization causes them to activate rapidly and then inactivate (voltage-gated).


Calcium currents (ICa)

Properties of Ca2+ channels are mainly determined by the principle (CaV) subunit, which has a structure like that of the NaV subunit of voltage-gated sodium channels.


High voltage activated (HVA) Calcium Currents (ICa)

1. L-type channels: CaV 1.1, 1.2, 1.3, 1.4 ……2. Neuronal channels: CaV2.1, 2.2, 2.3


Low voltage activated (LVA) Calcium Channels

T-type channels: CaV3.1, 3.2, 3.3


L-type calcium channels containing CaV1.2

Predominant in ventricular & atrial myocardium and cells of SA & AV nodes and conductive pathways


L-type channels containing CaV1.3

Expressed alongside predominant Cav1.2 in SA nodal cells


L-type channels – activation & inactivation

Activate rapidly in response to depolarization & subsequently inactivate in a manner dependent both on voltage (voltage-dependent inactivation, VDI) and cytoplasmic calcium (calcium-dependent inactivation, CDI).


Locations of L-type channels (besides in the heart)

Expressed in smooth & skeletal muscle and in the nervous system.


L-type calcium currents (ICa-L) are blocked by…

Dihydropyridines (nifedipine, for example) ----- used as anti-hypertensive agents
--- I-CaL channels are called dihydropyridine receptors (DHPR)


HVA (High voltage activated) vs. LVA (Low voltage activated) channels

LVA (T-type channels) means they are activated by weaker depolarizations than those required for activation of HVA channels (L-type and Neuronal).


I-CaL type vs. I-CaT type channels - activation dependint on

I-CaL both voltage- & Ca2+- dependent.....I-CaT are only voltage-dependent


T-type channels location

Expressed in SA node & in nervous system


Potassium channels - subunits

Unlike Na+ & Ca2+ channels, the principle subunits of K+ channels assemble as tetramers. Multiple genes encode subunits of the tetrameric channels, and in some instances hetero-tetramerization may occur between these gene products.


Time-dependent potassium currents

IKto (Kv4.3 tetramer + KChiP2) ......AND........ IKr (HERG tetramer + miRP1) ......AND..... IKs (KvLQT1 tetramer + mink)


IKto – (Kv4.3 tetramer + KChiP2) – activation & inactivation

Voltage-dependent inactivation (Depolarization causes both activation & inactivation on a time scale only slightly slower than that of sodium current.)


IKr (HERG tetramer + miRP1) & IKs (KvLQT1 tetramer + minK)

“Rapid” delayed rectifier and “slow” delayed rectifier, respectively. Depolarization causes activation of these two currents on a time scale of 20-100 ms.


Inward Rectifier potassium currents

IK1 and IKACh


IK1 - type of channel, type of tetramer

An “inward rectifier” channel (Kir tetramer)


IK1 - gating

Not gated in conventional sense, but its conductance is steeply voltage-dependent as a consequence of block by cytoplasmic constituents ---> these channels display a strong, “instantaneous” (


IK1 – action

Hold cells near EK btwn APs w/out producing an outward current upon depolarization that would be energetically costly & make it more difficult to generate an AP


IKACh - channel type, tetramer type

An “inward rectifier channel” (GIRK tetramer)


IKACh increase & role

Increased by activation of muscarinic receptors (in response to ACh) = Important for ability of parasympathetic nervous system to slow pacemaker activity of the SA node.


Non-selective / Time-dependent cation current

If (or Ih)


If (or Ih) - activation/inactivation

Considered “funny” (hence the “f“) b/c it is turned off at depolarized potentials & turned on at hyperpolarized potentials (hence the “h” in Ih)….. Permeable to both Na+ & K+ (Erev ~ -30 mV)


If (Ih) role

Possibly plays important role in pacemaking SA nodal cells


Categorization of cardiac APs as fast or slow is based on…

… whether the initial upstroke is rapid or slow


Phase 0 of Fast Cardiac APs

Initial upstroke (phase 0) consists of rapid depolarization caused by entry of Na+ (INa) through voltage-activated sodium channels. The rapid upstroke of fast cardiac APs is an indicator of the much faster spatial propagation than occurs for slow action potentials.


Phases 1 of Fast Cardiac APs

Following the rapid upstroke (phase 0) is a small, partial repolarization (phase 1), which is produced by a combination of inactivation of sodium current & activation of a transient potassium current IKto.


Phase 2 of Fast Cardiac APs

After the repolarization brough on in phase 1 by the inactivation of Na current and activation of IKto, phase 2 occurs with a prolonged plateau, during which voltage-activated, L-type calcium channels are open….The influx of Ca2+ (ICa-L) is ~balanced by an efflux of K+ (IKr and IKs) via delayed rectifier channels so that membrane potential remains at a roughly constant level (near 0 mV) during the plateau.


Phase 3 of Fast Cardiac APs

After the plateau of Phase 4, the combination of inactivation of (ICa) and increased activation of IKr and IKs causes termination of the plateau by a rapid repolarization (phase 3).


Phase 4 of Fast Cardiac APs

As a result of the rapid repolarization of phase 3, IKr and IKs are de-activated, and inactivation of INa and ICa is removed; the cell is held near EK by the inward rectifier (IK1)


Initiation of a second AP

A second action potential cannot be initiated (absolute refractory period) until most of the inactivation of INa is removed (during the repolarizing phase), and the threshold for a second APs remains elevated (relative refractory period) until after repolarization is complete (complete removal of inactivation of INa and deactivation of IKr and IKs has occurred).


Differences between ionic currents in pacemaker cells of SA & AV nodes and those in cells of the myocardium & fast conducting pathways.

Most notably, pacemaker cells have reduced INa & little IK1…Also, pacemaker cells express If and ICa-T which are essentially absent in myocardial cells.


Result of the complement of ionic currents expressed in pacemaker cells

No stable resting potential; These cells produce repetitive, “slow action potentials.”


Phase 0 of Slow Cardiac APs

An upstroke attributable to activation of ICa-T and ICa-L, which is relatively slow owing to the absence of INa.


Phase 1 & 2 in Slow Cardiac APs

Slow cardiac action potentials lack the partial repolarization (phase 1) & prolonged plateau (phase 2) characteristic of fast action potentials


Phase 3 in Slow Cardiac APs

Rather than phases 1&2 (partial repolarization & prolonged plateau) of fast cardiac APs, the balance between ICa and delayed rectifier current (IKr & IKs) is such that repolarization (phase 3) occurs shortly after the peak of the action potential.


Phase 4 of Slow Cardiac APs

Repolarization in Phase 3 is followed by a slow depolarization (the “pacemaker potential”) during phase 4, which brings the cell back to threshold for the generation of another AP


Pacemaker potential & If (funny current)

One contributor of likely importance to the pacemaker potential is the funny current (If) which is induced by hyperpolarization ---> allows cation fluxes (Na+ and to a slightly lesser extent K+) ---> drive voltage towards the reversal potential of If (-30 mV)


Pacemaker potential – other current contributors (other I’s than If)

The pacemaker depolarization during phase 4 of slow cardiac action potentials is also likely facilitated by the slow deactivation of IKr and IKs, and by activation of LVA Ca2+ current (ICa-T).


Rhythmic firing of pacemaker cells

1. Ion channels present in plasma membrane of pacemaker cells provide highly plausible mechanism for rhythmic firing……..2. Also suggested that INTERNAL CALCIUM RELEASE & the resultant movements of Na+ and Ca2+ via NCX SODIUM/CALCIUM EXCHANGER play an important role in generating the pacemaker potential


IKr (tetramer of HERG) & preclinical evaluation of new drugs

B/c of its importance for repolarization of both fast & slow cardiac action potentials, altered HERG function can disrupt normal cardiac electrical activity, leading to arrhythmias === significant in regard to clinically administered drugs b/c HERG channels are blocked by a wide variety of structurally unrelated compounds…..Thus, now standard practice that early pre-clinical tests of any investigational drug must determine whether it blocks HERG channels.


Ion channel basics

1. Channels "gate" open/closed. 2. Direction of current flow depends on membrane potential (Vm) & ion gradient (Nernst potential, E-ion). 3. Current flowing into cell causes depolarization; Current flowing out causes hyperpolarization


Vm vs. E-ion and direction of ion flow

If VmE-ion, current flows out of the cell


Locations of slow APs

SA node, AV node


Locations of fast APs

Myocardium, ventricular muscles, specialized conductive pathways (such as Purkinje fibers)


Difference between fast & slow APs depends on

Types of ion channels in these tissue types


Nernst potential (E-ion) of Na, Ca, K

E-Na = +58…..E-Ca = +124……E-K = -90


Direction of propagation of APs in the heart is controlled by…

Gap junction position & by connective tissue “insulation” (btwn atria & ventricles)


Channel structure:

Pore w/activation gate (voltage-gated; open when voltage becomes more positive) on intracellular side


Activation of I-Na, I-Ca-L, I-Ca-T

Current (+charge movement) is always inward b/c can’t be more positive than E-Na or E-Ca (If VmE-ion, current flows out)


Activation of transient inward outward I-K

Always outward (positive charge exits) b/c can’t get to voltage more negative than E-K (If VmE-ion, current flows out)


Currents during the Phases of FAST Cardiac AP

Phase 0 = I-Na (activates then inactivates again)……Phase 2 = I-Ca-L (long lasting)……..Phase 1 = transient outward current I-Kto………..Phase 3 = I-Kr & I-Ks delayed rectifier current……. Phase 4 = I-K1 inward rectifier current (see slide 12)


Currents during the Phases of of SLOW Cardiac AP

Phase 0 – activation of I-CaT & I-CaL………. Phase 3 = If…….Phase 4 = I-Kr, I-Ks delayed rectifier currents


Pacemaker depolarization - what it is & how it is accomplished

Spontaneous tendency to depolarize & create APs

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