K1

Most of the important channels in the heart provide voltage-gated currents. A single gene encodes for alpha subunits that can provide current, although relatively normal behavior requires coexpression with beta subunits. However, the full range of normal behavior of currents requires the products of multiple genes.

Ion channels appear to have evolved from a primitive ion channel structure similar to the potassium inward-rectifier channel. Although many mutations have been found they rarely have consequences. In most channel types a loop between the 5th and 6th a helices (S5 and S6) enters the membrane to form a P loop. The pore region for all potassium channels has a signature motif conferring selectivity around an inverted cone, whereas for sodium and calcium channels, selectivity is conferred by four amino acids, one from each P loop. These are glutamate in calcium channels. Voltage-sensing regions are found in voltage-dependent channels. These regions contain regularly spaced arginine or lysine at every third amino acid in the transmembrane portions of the channels.

Ideally, intimate molecular knowledge of the different channels makes it possible to tailor small molecules to bind specifically to particular binding sites in specific channels in a manner analogous to targeting active sites in enzymes. Such targeting should make it possible in the future to achieve any desired level of specificity for ion channel modulating actions (activation or blocking) on the different types and subtypes of cardiac ion channels, but currently this cannot be done. Many of the current channel blockers lack specificity for particular channels. For example, verapamil blocks sodium as well as calcium channels; some sodium channel blockers block potassium channels while many potassium channel blockers fail to differentiate between the subtypes of potassium channels. The IKr potassium channel is particularly promiscuous in that it is blocked by a multitude of different class and chemical types of drugs, although many of them appear to bind somewhere on the signature motif on its inverted cone. The more we understand the molecular structure of the voltage dependent cardiac ion channels, the greater is our expectation of creating ion channel modulators with very specific binding, resulting in selective actions against arrhythmias. The process of inactivation can be viewed as being of two types:

1. N-type, or ball and chain, where an amino acid 'ball' swings into the intracellular mouth of pore of the previously opened channel.

2. C-type, which involves allosteric changes in the channel to terminate ion permeation.

Such models may be overly simplistic in that there are probably more than two types of inactivation with varying time courses.

Many naturally occurring toxins block channels by binding at extracellular sites and thereby disrupting ion movement by allosterically preventing opening, whereas synthetic small molecules may bind to relatively specific sites in channels where access to the sites are determined by channel state (e.g., S6 segment lining the pore) for sodium, potassium, and some calcium channels.

6.33.2.1.1 Sodium channels

Sodium channels as a family are encoded by nine genes for highly homologous a subunits with two ancillary beta subunits (b1 and b2 subunit) that are encoded by four genes. Together variations on this theme result in the different voltage and time dependent sodium channels found in various tissues.6 The gene for the cardiac form of the sodium channel - SCN5A (2016 amino acid) - is located on chromosome 3p21.7 The function of this channel is activation in atrial, His/Purkinje, and ventricular tissue. The S4 regions function as voltage sensors which lead to voltage dependent opening of the channel, and this action initiates time dependent coupled inactivation, although it is also possible for the channel to change directly from open to inactivated state. Tetrodotoxin, at nanomolar concentrations, characteristically blocks voltage and time dependent neuronal sodium currents although the cardiac form requires higher concentrations (1-10 mM). This difference is due to cysteine in position 373 in the heart form of the channel versus an aromatic residue in other forms.7

Mutations of SCN5A, including the LQT3 variant, are responsible for some of the genetic forms of long QT in the ECG.6'7 These mutations cause a failure of fast inactivation. Mutations occurring at a variety of sites also produce the same ECG pathology. Other mutations cause idiopathic ventricular fibrillation, conduction block, and ventricular fibrillation associated with a J point aberration of the ECG (Brugada syndrome).

6.33.2.1.2 Calcium channels

Calcium channels exist in various forms (T, L, N, P, and Q) depending upon tissue type.8 The dominant channel in the heart is L (large)-type calcium channel, with minor presence of T-type. Ten genes encode the main Cava1 subunit of the voltage gated calcium channel with three major subfamilies: Cav1a1, Cav2a1, and Cav3a1. Neurons contain N, P/Q, and R type channels. The L-type channel is b-adrenoceptor-dependent since beta-adrenoceptor activation, via a cAMP dependent protein kinase, increases the L-type current and shifts activation toward the pacing range.

The L-type channel is highly voltage dependent and contains Cavlal subunits. It activates relatively slowly, but deactivates faster, shows weak voltage dependent inactivation, marked calcium dependent inactivation, and sensitivity to the dihydropyridine class of calcium channel blocking drugs. Conduction through the SA and AV nodes is critically dependent upon L-type calcium activation, as is the coupling of excitation to contraction in cardiac cells. The T-type channel is characterized by low voltage dependent characteristics. It has pronounced voltage dependent inactivation, is insensitive to dihydropyridines, and absent in ventricular tissue, but present in pacing cells and some atrial cells. It could contribute to pacemaking during the slow pacing depolarization seen in SA nodes.

Other types of channels include calcium activated currents such as ICl(Ca) which is a Ca2 + activated Cl_ current, and the Ca2 + activated nonselective cation current INS(Ca). The Na+/Ca2 + exchanger produces an INa/Ca current which is dependent upon membrane potential, and Ca2 + and Na+ concentrations. INa/Ca is important in all cardiac cells, both as a Ca2 + transporter, and in pacing and arrhythmogenic current generation.

6.33.2.1.3 Potassium channels

Potassium channels are responsible for generating repolarization currents and maintaining resting membrane potentials.9 The resting potential is negative since only potassium channels are open at rest and potassium concentrations are high ([K]I = 140 mM) inside cells versus the outside ([K]o = 3.5 mM). All K+ currents carry outward currents which serve to repolarize or stabilize resting potentials. These currents are divided into voltage activated or ligand activated currents and nongated currents: the voltage activated currents are Ito, IKur, IK„ IKs, and IKss; the ligand activated currents IKATP IKACh, IKNa, and IKAA; and the nongated (background) currents IK1.

The genes for most K+ channels are known. Their molecular structure is analogous to Na+ and Ca2 + channels. There is one domain with six transmembrane segments in which segment four (S4) acts as a voltage sensor. Voltage activated channels have N- and C-type inactivation where the C-type is sensitive to drugs and [K]o. The ligand activated and background channels have only two transmembrane segments while the pore of the channel is located in the S5-S6 link.9

6.33.2.1.3.1 The main voltage activated K currents: Ito, IKur, IKr, IKs, and IKss

The transient outward K+ current (Ito) occurs in most human cardiac tissue and is the major repolarizing current in mice and rat atrial and ventricular cells. It is also present in brain and pancreas. It is blocked by some antiarrhythmic drugs and regulated by glucocorticoids

The ultra rapid delayed rectifier (IKur-Kv1.5) is selectively present in human and dog atrium, and in all chambers of rat and mouse hearts. The gene for the rapid component of the delayed rectifier channel (IKr) includes the human ether-a-go-go (hERG) gene that encodes the a subunit. It is most abundant in the heart, but also occurs in the hippocampus. Its amino acid sequence is highly conserved across mammals. As is discussed in detail later, the IKr channel is blocked by many different drugs of different chemical types and classes, resulting in a potential for causing torsades de pointes. The first major example of this occurred with the long-acting H1 antihistamines astemizole and terfenadine, which were unexpectedly observed to cause death, apparently due to sudden cardiac death, and the occurrence of torsades. The occurrence of torsades is related directly to prolongation of the QT interval of the ECG due to blockade of IKr. The slow component of the delayed rectifier (IKJ is also coexpressed in some species. Guinea pigs, humans, and dogs have both forms, and cats and rabbits primarily IKP IKs is revealed by blockade of IKr current. IK is a slowly activating outward current found in the heart and inner ear. Activation of this current may account for the action potential narrowing due to b-adrenoceptor activation, and acts to counter the increase in ICa seen with such activation. Mutation induced dysfunction of this channel may explain the increased arrhythmogenic actions of catecholamines seen in some arrhythmia phenotypes.

6.33.2.1.3.2 Ligand activated K currents include IKatp, IKACh, IKNa, and IKaa

The ATP dependent K+ current (IKATP) consists of coexpressed Kir6.x with an attached sulfonylurea (antidiabetic drug) receptor.9 The cardiac channel is a heteromultimeric form of Kir6.2 plus the 2A form of the sulfonylurea receptor found in both cell plasma membrane and mitochondrial membranes. The channel is activated by low levels of ATP or by nicorandil/pinacidil, drugs that lower channel affinity for ATP. Its channel kinetics are very complex and the sensitivity to low ATP is increased by acid, ADP, and lactate. To close the channel a critical concentration of ATP is required in the immediate vicinity of the channel. It is this channel that regulates the release of insulin in the b cells of the islets of Langerhans.

6.33.2.1.3.3 The K+ channel activated by the cholinergic transmitter acetylcholine (ACh) acting on muscarinic

(M2 subtype) cholinoceptors This channel (IKACh) consists of Kir3.1 and 3.4 (GIRK1 and GIRK4) in heart.9 Acetylcholine activates muscarinic (M2) receptors and the Gby pathway. The channel is predominantly expressed in nodes and atrial tissues, i.e., those exposed to ACh released from parasympathetic nerves that slow heart rate and conduction through the AV node. The channel is very selective for potassium ions and is sensitive to [K]o. IKACh plays a role in atrial fibrillation since vagal stimulation leads to its activation and reduction of atrial refractoriness, and therefore increased liability to arrhythmias.

6.33.2.1.3.4 The sodium activated K+ channel

This channel (IKNa) is a Na+ -gated K+ channel activated by high Na+. It has two open states, but sometimes the channel is silent for minutes. It has a high selective conductance for K+ ions (200pS) that is blocked by Rb + or Cs +.

6.33.2.1.3.5 The fatty acid and amphiphile activated K+ channel

This channel (IKaA is activated by arachidonic and other unsaturated fatty acids (in rats) and has two possible pores.

6.33.2.1.3.6 The inward rectifier K+ channel

This channel (IK1) is part of the Kir superfamily of potassium channels that subserve many physiological functions. The Kir2.x family consists of two transmembrane segments with a pore sequence.9 In the heart, the IK1 channel is important for maintaining resting negative membrane potential in all cardiac cells (except nodes), and participates in terminal repolarization. The highest density of channels is in Purkinje and ventricular cells with a lower density in atria (which has a corresponding lower resting membrane potential). They are almost absent in nodal cells. The inward rectification property of IK1 results from a block of outward current by intracellular substances (Mg2 + and polyamines). It is selective for K+ and regulated by [K]o.

6.33.2.1.3.7 Other K+ currents

These include the 'funny' (f) or hyperpolarizing (h) pacemaker current (If, Ih). Ih is a member of the HCN family with subtypes 1 and 4 occurring in the heart.10 The channel has poor selectivity for Na + or K+ ions, and a reversal potential of — 10 to — 20 mV HCN has the typical six membrane spanning unit with a S4 voltage sensor. It is regulated by cyclic nucleotide signaling, down via mucarinic receptors and up via ^-adrenoceptors. The mechanism underlying its hyperpolarization-induced activation is unknown.

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