Alignment of herg potassium channel with known structures of potassium channel Name: Prachi Sharma Superviser: Prof. Gert Vriend introduction

1.1.2 POTASSIUM CHANNEL 2TM

Four of these subunits cluster to form the active channel. Each subunit is composed of two membrane-spanning helices M1 and M2 that flank a P segment. P segment transverses only the outer portion of the transmembrane region (Fig 4).

Fig4:a | Schematic drawing of a Kir channel subunit. Each subunit comprises two transmembrane helices (M1 and M2), a pore-forming region containing the pore-helix (P), and a cytoplasmic domain formed by the amino (N) and carboxy (C) termini. b | View of the tetrameric structure of the KirBac1.1 channel⁴ (PDB ID: 1P7B) from the extracellular side. Monomers are individually coloured red, green, yellow and blue. A K⁺ ion (white) indicates the conduction pathway. c | Side view of the KirBac1.1 structure showing the transmembrane domain of two subunits (green and blue) and the C-terminal domains of their neighbouring subunits (red and yellow). White spheres represent K⁺ ions in the selectivity filter. Source: http://www.nature.com/nrn/journal/v4/n12/images/nrn1244-f1.jpg

Vertebrate 2TM inward rectifier subunits can be grouped into at least six subfamilies termed Kir1 through Kir6 (Doupnik et al., 1995).

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Inward-rectifier potassium ion channel: They are two transmembrane potassium channels. Under equal but opposite electrochemical potentials, they allow K ion influx but little potassium ion out flux so called Inward-rectifier potassium ion channel. Inward rectfication is mainly due to the blockade of outward current by internal Mg ion. They are ATP sensitive open when ATP is low. They are important for maintenance of prolong depolarization which generate prolong action potential in heart. They also prevent excessive hyperpolarization (11).

The closed state. During the process of rectification, the flow of K⁺ ions from a cell is temporarily blocked by Mg²⁺ or polyamines. This is not the same as the channel's being closed. Reversal of the applied voltage or an increase of the external K⁺ concentration can remove the block. This channel is in the closed state because the ion-conduction pathway is blocked by the side chains of one of the Phe. We call this amino acid the "blocking residue" for structural reasons, but it is likely to be the "activation gate" in electrophysiological terms. The sequence alignment of Kir channels indicates that residues with large hydrophobic aromatic or aliphatic side chains are favored in this position (12).

1.1.3 POTASSIUM CHANNEL 4TM

There are K⁺ channel alpha-subunits that possess two P-domains (Fig 5).



Fig5:TM with two pores first pore between M1 and M2 and second pore between M3 and M4. Source:http://www.nature.com/nrn/journal/v3/n2/images/nrn727-f1.gif

These are usually highly regulated K⁺ selective leak channels. They are two-pore-domain K(+) channels, or K(2P) channels They have four transmembrane segments and are active as dimers. They play a major role in setting the resting membrane potential in many cell types (13).These channels encode K⁺ selective background conductances that are voltage-independent . Sequencing of the genomes of Caenorhabditis elegans and Drosophila have revealed that 50 of 80 and 11 of 30 K⁺

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channel genes belong to the 2P domain family, respectively (12). Different subclasses of this type of potassium channels are TWIK, TRAAK, TREK, TASK.

1.1.3.1 TREK

Human TREK channels are highly expressed in the central and peripheral nervous systems, but are absent from the heart. TREK channels are opened by a variety of physical and chemical stimuli (14). TREK-1 is highly expressed in temperature-sensitive neurons of the preoptic hypothalamus and dorsal root ganglions and moreover is activated by heat

1.1.3.2 TWIK

These are weakly inward rectifying K+ channel. TWIK 1 is expressed in kidney cells . TWIK-2 is highly expressed in the gastrointestinal tract, the vasculature, and the immune system. TWIK-2 currents exhibit outward rectification (15).

1.1.3.3 TRAAK

Despite having a Two pore and four Transmembrane topology it display little sequence identity (about 25%) with other 2P/4TM potassium channels. TRAAK has a shorter amino-terminal region but a larger C terminus region. It has a large extracellular loop between M1 and P1, with a cysteine residue. This protein is expressed in brain, retina, and spinal cord . The most intense levels of expression are present in the olfactory system, cerebral cortex, hippocampal formation, habenula, basal ganglia, and cerebellum (16).

1.1.3.4 TASK

TASK subunits are background K⁺ channels that are inhibited by mild external acidosis . The opening of TASK-1 is stimulated by inhalational anesthetics including halothane and isoflurane . TASK-1 has been recently proposed to encode the background K⁺ channel present in motoneurons, cerebellum granular cells, and type I carotid body cells (15).

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