Pathways & interactions
Potassium channel, inwardly rectifying, Kir6.2 (IPR003279)
Short name: K_chnl_inward-rec_Kir6.2
- Potassium channel, inwardly rectifying, Kir (IPR016449)
- Potassium channel, inwardly rectifying, Kir6.2 (IPR003279)
Potassium channels are the most diverse group of the ion channel family [PMID: 1772658, PMID: 1879548]. They are important in shaping the action potential, and in neuronal excitability and plasticity [PMID: 2451788]. The potassium channel family is composed of several functionally distinct isoforms, which can be broadly separated into 2 groups [PMID: 2555158]: 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 [PMID: 2448635]. 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 [PMID: 1373731]. In prokaryotic cells, they play a role in the maintenance of ionic homeostasis [PMID: 11178249].
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) [PMID: 11178249]. 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.
Inwardly-rectifying potassium channels (Kir) are the principal class of two-TM domain potassium channels. They are characterised by the property of inward-rectification, which is described as the ability to allow large inward currents and smaller outward currents. Inwardly rectifying potassium channels (Kir) are responsible for regulating diverse processes including: cellular excitability, vascular tone, heart rate, renal salt flow, and insulin release [PMID: 10102275]. To date, around twenty members of this superfamily have been cloned, which can be grouped into six families by sequence similarity, and these are designated Kir1.x-6.x [PMID: 7580148, PMID: 10449331].
Cloned Kir channel cDNAs encode proteins of between ~370-500 residues, both N- and C-termini are thought to be cytoplasmic, and the N terminus lacks a signal sequence. Kir channel alpha subunits possess only 2TM domains linked with a P-domain. Thus, Kir channels share similarity with the fifth and sixth domains, and P-domain of the other families. It is thought that four Kir subunits assemble to form a tetrameric channel complex, which may be hetero- or homomeric [PMID: 10102275].
Kir6.x inward rectifier K+ channel family subunits associate with sulphonylurea receptors (SURs) to form ATP-sensitive K+ (KATP) channels. These are octameric complexes containing equal numbers of Kir and SUR subunits. The resulting channels are regulated by cytosolic nucleotides, such as ATP, and thus link cell metabolism to electrical activity, and K+ fluxes. They are important in the regulation of insulin secretion, the control of vascular and smooth muscle tone, and the response of the heart (and possibly the brain) to ischaemia.
Kir6.2 (also known as BIR/KATP) is thought to associate with SUR1 to form the pancreatic beta cell KATP channel that is involved in regulation of insulin secretion. Combination of Kir6.2 with splice variants of SUR2 is thought to produce the cardiac and smooth muscle KATP isoforms [PMID: 9683320].