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.
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
The phenomenon of inward rectification of Kir channels is the result of high-affinity block by endogenous polyamines, namely spermine, and magnesium ions that plug the channel pore at positive potentials, resulting a decrease in outward currents. This voltage-dependent block by polyamines causes currents to be conducted well in the inward direction. While the principal idea of polyamine block is understood, the specific mechanisms are still controversial.
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:
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.
Kir channels are involved in regulation of nitric oxide synthase.
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.
Kir2.2, Kir4.1, PSD-95, SAP97, AKAP79
Kir2.1 and Kir2.3 to form heteromeric channel, auxiliary subunit: SAP97, Veli-1, Veli-3, PSD-95
Kir2.1 and Kir2.3 to form heteromeric channel, PSD-95, Chapsyn-110/PSD-93
Kir2.1 to form heteromeric channel
Kir3.2, Kir3.4, Kir3.5, Kir3.1 is not functional by itself
Kir3.1, Kir3.3, Kir3.4 to form heteromeric channel
Kir3.1, Kir3.2 to form heteromeric channel
Kir3.1, Kir3.2, Kir3.3
Kir4.2, Kir5.1, and Kir2.1 to form heteromeric channels
SUR1, SUR2A, and SUR2B
Diseases related to Kir channels
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)
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).
Cardiac action potential#Major channels
^ ab 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 Rev57 (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 J13 (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.