Two pore domain potassium channel, TWIK-1 (2pore_dom_K_chnl_TWIK1)
Type: Family

Potassium channels are the most diverse group of the ion channel family . They are important in shaping the action potential, and in neuronal excitability and plasticity . The potassium channel family is composed of several functionally distinct isoforms, which can be broadly separated into 2 groups : the practically non-inactivating 'delayed' group and the rapidly inactivating 'transient' group.

These are all highly similar proteins, with only small amino acid changes causing the diversity of the voltage-dependent gating mechanism, channel conductance and toxin binding properties. Each type of K
+
channel is activated by different signals and conditions depending on their type of regulation: some open in response to depolarisation of the plasma membrane; others in response to hyperpolarisation or an increase in intracellular calcium concentration; some can be regulated by binding of a transmitter, together with intracellular kinases; while others are regulated by GTP-binding proteins or other second messengers . In eukaryotic cells, K
+
channels are involved in neural signalling and generation of the cardiac rhythm, act as effectors in signal transduction pathways involving G protein-coupled receptors (GPCRs) and may have a role in target cell lysis by cytotoxic T-lymphocytes . In prokaryotic cells, they play a role in the maintenance of ionic homeostasis .

All K
+
channels discovered so far possess a core of alpha subunits, each comprising either one or two copies of a highly conserved pore loop domain (P-domain). The P-domain contains the sequence (T/SxxTxGxG), which has been termed the K
+
selectivity sequence. In families that contain one P-domain, four subunits assemble to form a selective pathway for K
+
across the membrane. However, it remains unclear how the 2 P-domain subunits assemble to form a selective pore. The functional diversity of these families can arise through homo-or hetero-associations of alpha subunits or association with auxiliary cytoplasmic beta subunits. K
+
channel subunits containing one pore domain can be assigned into one of two superfamilies: those that possess six transmembrane (TM) domains and those that possess only two TM domains. The six TM domain superfamily can be further subdivided into conserved gene families: the voltage-gated (Kv) channels; the KCNQ channels (originally known as KvLQT channels); the EAG-like K
+
channels; and three types of calcium (Ca)-activated K
+
channels (BK, IK and SK) . The 2TM domain family comprises inward-rectifying K
+
channels. In addition, there are K
+
channel alpha-subunits that possess two P-domains. These are usually highly regulated K
+
selective leak channels.

2P-domain channels influence the resting membrane potential and as a result can control cell excitability. In addition, they pass K+ in response to changes in membrane potential, and are also tightly regulated by molecular oxygen, GABA (gamma-aminobutyric acid), noradrenaline and serotonin.

The first member of this family (TOK1), cloned from Saccharomyces cerevisiae , is predicted to have eight potential transmembrane (TM) helices. However, subsequently-cloned two P-domain family members from Drosophila and mammalian species are predicted to have only four TM segments. They are usually referred to as TWIK-related channels (Tandem of P-domains in a Weakly Inward rectifying K+ channel) . Functional characterisation of these channels has revealed a diversity of properties in that they may show inward or outward rectification, their activity may be modulated in different directions by protein phosphorylation, and their sensitivity to changes in intracellular or extracellular pH varies. Despite these disparate properties, they are all thought to share the same topology of four TM segments, including two P-domains. That TWIK-related K+ channels all produce instantaneous and non-inactivating K+ currents, which do not display a voltage-dependent activation threshold, suggests that they are background (leak) K+ channels involved in the generation and modulation of the resting membrane potential in various cell types. Further studies have revealed that they may be found in many species, including: plants, invertebrates and mammals.

TWIK family members (TWIK-1 and TWIK-2) produce constitutive K+ currents of weak amplitude . They are present in a variety of tissues, including brain and cells of the immune system. Together with their functional properties, their wide distribution suggests that these channels may be involved in the control of background K+ conductances in many cell types.

TWIK-1 was the first two P-domain K
+
channel subunit cloned from human tissue . It is widely distributed, being particularly abundant in the brain and heart. It forms a weak inward rectifer K
+
channel, and has been found to be inhibited by internal acidification; its activity is enhanced by protein kinase C phosphorylation.