Inward-rectifier potassium ion channel

Inwardly rectifing potassium channels (K_ir, IRK) are potassium selective ion channels. To date, seven subfamilies have been identified in various mammalian cell types.^[1] They are the targets of multiple toxins, and malfunction of the channels has been implicated in several diseases.^[2]

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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

The phenomenon of inward rectification of K_ir 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 K_ir channels

K_ir 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:

Biochemistry of K_ir channels

There are seven subfamilies of K_ir channels, denoted as K_ir1 - K_ir7.^[1] Each subfamily has multiple members (i.e. K_ir2.1, K_ir2.2, K_ir2.3, etc) that have nearly identical amino acid sequences across known mammalian species.

K_ir 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 K_ir2.1 and K_ir2.3) when the channels are overexpressed.

Diversity

Diseases related to K_ir channels

• Persistent hyperinsulinemic hypoglycemia of infancy is related to autosomal recessive mutations in K_ir6.2. 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 K_ir 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 K_ir2.1. 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 K_ir channels.

• Atherosclerosis (heart disease) may be related to K_ir channels. The loss of K_ir currents in endothelial cells is one of the first known indicators of atherogenesis (the beginning of heart disease).

See also

• Cardiac action potential#Major channels

References

1. ^ ^{a b} 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.
2. ^ Abraham MR, Jahangir A, Alekseev AE, Terzic A (1999). "Channelopathies of inwardly rectifying potassium channels". FASEB J 13 (14): 1901-10. PMID 10544173.
3. ^ 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.