Inward-rectifier potassium ion channel
Editor-In-Chief: C. Michael Gibson, M.S., M.D. 
Inwardly rectifing potassium channels (Kir, IRK) are potassium selective ion channels. To date, seven subfamilies have been identified in various mammalian cell types. They are the targets of multiple toxins, and malfunction of the channels has been implicated in several diseases.
Definition of inward rectification
These channels are termed inwardly rectifying - because they rectify current (positive charge) in the inward direction. This means that under equal but opposite electrochemical potentials, these channels will pass more inward current than they do outward, as in figure 1. In the figure, there is more current passed inward (negative) than outward (positive). In fact, the individual positive traces are difficult to discern. The current is created by the flow of K+ ions down their electrochemical gradient. However, the conductance of potassium ions is enhanced at more negative membrane potentials and is blocked when the cell is more depolarized. Under physiological conditions, these channels allow outward flow of potassium ions only when cells are 20 mV above the resting potential or lower. Thus in cells with a -60 mV resting potential, these channels would not conduct current at membrane potentials greater than -40 mV.
Mechanism of inward rectification
Inward rectification of Kir channels is the result of high-affinity block by endogenous polyamines, namely spermine, and magnesium ion that plug the channel pore at more positive potentials. While the principal idea of polyamine block is understood, the specific mechanisms are unknown. Thus when the membrane potential becomes less negative (depolarization), the channel is blocked and the efflux of potassium is limited. This decreased outward current (with inward current unaffected) results in more net current being passed inward than outward; hence inward-rectification of the current.
Role of Kir channels
Kir channels are found in multiple cell types, including macrophages, cardiac and kidney cells, leukocytes, neurons and endothelial cells. Their roles in cellular physiology vary across cell types:
|cardiac myocytes||Kir channels close upon depolarization, slowing membrane repolarization and helping maintain a more prolonged action potential. This type of inward-rectifier channel is distinct from delayed rectifier K+ channels, which help re-polarize nerve and muscle cells after action potentials; and potassium leak channels, which provide much of the basis for the resting membrane potential.|
|endothelial cells||Kir channels are involved in regulation of nitric oxide synthase.|
|kidneys||Kir export surplus potassium into collecting tubules for removal in the urine, or alternatively may be involved in the reuptake of potassium back into the body.|
|neurons and in heart cells||G-protein activated IRKs (Kir3) are important regulators. A mutation in the GIRK2 channel leads to the weaver mouse mutation. "Weaver" mutant mice are ataxic and display a neuroinflammation-mediated degeneration of their dopaminergic neurons. Weaver mice have been examined in labs interested in neural development and disease for over 30 years.|
|pancreatic beta cells||KATP channels (comprised of Kir6.2 and SUR1 subunits) control insulin release.|
Biochemistry of Kir channels
There are seven subfamilies of Kir channels, denoted as Kir1 - Kir7. Each subfamily has multiple members (i.e. Kir2.1, Kir2.2, Kir2.3, etc) that have nearly identical amino acid sequences across known mammalian species.
Kir channels are formed from as homotetrameric membrane proteins. Each of the four identical protein subunits is composed of two membrane-spanning alpha helices (M1 and M2). Heterotetramers can form between members of the same subfamily (ie Kir2.1 and Kir2.3) when the channels are overexpressed.
|KCNJ2||Kir2.1||IRK1||Kir2.2, Kir4.1, PSD-95, SAP97, AKAP79|
|KCNJ12||Kir2.2||IRK2||Kir2.1 and Kir2.3 to form heteromeric channel, auxiliary subunit: SAP97, Veli-1, Veli-3, PSD-95|
|KCNJ4||Kir2.3||IRK3||Kir2.1 and Kir2.3 to form heteromeric channel, PSD-95, Chapsyn-110/PSD-93|
|KCNJ14||Kir2.4||IRK4||Kir2.1 to form heteromeric channel|
|KCNJ3||Kir3.1||GIRK1, KGA||Kir3.2, Kir3.4, Kir3.5, Kir3.1 is not functional by itself|
|KCNJ6||Kir3.2||GIRK2||Kir3.1, Kir3.3, Kir3.4 to form heteromeric channel|
|KCNJ9||Kir3.3||GIRK3||Kir3.1, Kir3.2 to form heteromeric channel|
|KCNJ5||Kir3.4||GIRK4||Kir3.1, Kir3.2, Kir3.3|
|KCNJ10||Kir4.1||Kir1.2||Kir4.2, Kir5.1, and Kir2.1 to form heteromeric channels|
|KCNJ11||Kir6.2||KATP||SUR1, SUR2A, and SUR2B|
- Persistent hyperinsulinemic hypoglycemia of infancy is related to autosomal recessive mutations in Kir6.2. Certain mutations of this gene diminish the channel's ability to regulate insulin secretion, leading to hypoglycemia.
- Bartter's syndrome can be caused by mutations in Kir channels. This condition is characterized by the inability of kidneys to recycle potassium, causing low levels of potassium in the body.
- Andersen's syndrome is a rare condition caused by multiple mutations of Kir2.1. Depending on the mutation, it can be dominant or recessive. It is characterized by periodic paralysis, cardiac arrhythmias and dysmorphic features. (See also KCNJ2)
- Barium poisoning is likely due to its ability to block Kir channels.
- Atherosclerosis (heart disease) may be related to Kir channels. The loss of Kir currents in endothelial cells is one of the first known indicators of atherogenesis (the beginning of heart disease).
- Inward+Rectifier+Potassium+Channels at the US National Library of Medicine Medical Subject Headings (MeSH)
- UMich Orientation of Proteins in Membranes families/family-85 - Spatial positions of inward rectifier potassium channels in membranes
- ↑ 1.0 1.1 Kubo Y, Adelman JP, Clapham DE, Jan LY, Karschin A, Kurachi Y, Lazdunski M, Nichols CG, Seino S, Vandenberg CA (2005). "International Union of Pharmacology. LIV. Nomenclature and molecular relationships of inwardly rectifying potassium channels". Pharmacol Rev. 57 (4): 509–26. doi:10.1124/pr.57.4.11. PMID 16382105.
- ↑ Abraham MR, Jahangir A, Alekseev AE, Terzic A (1999). "Channelopathies of inwardly rectifying potassium channels". FASEB J. 13 (14): 1901–10. PMID 10544173.
- ↑ Peng J, Xie L, Stevenson FF; et al. (2006). "Nigrostriatal dopaminergic neurodegeneration in the weaver mouse is mediated via neuroinflammation and alleviated by minocycline administration". J. Neurosci. 26 (45): 11644–51. doi:10.1523/JNEUROSCI.3447-06.2006. PMID 17093086.