Inward-rectifier potassium ion channel

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Inwardly rectifing potassium channels (K_ir, IRK) are a specific subset of 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]

[edit] Overview of inward rectification

Figure 1. Whole-cell current recording of a K_ir2 inwardly-rectifying potassium channel expressed in an HEK293 cell. There are 13 responses in this image. The bottom-most trace is a voltage step to 60mV below the resting membrane potential and the top-most to 60mV above the resting membrane potential. Other traces are in 10mV increments between the two.

A channel that is "inward-rectifying" is one that passes current (positive charge) more easily in the inward direction (into the cell). By convention, this inward current is considered a negative current, while an outward current (positive charge moving out of the cell) is considered a positive current.

At membrane potentials below the channel's resting potential, inwardly rectifying K⁺ channels support the flow of positive charge into the cell, pushing the membrane potential back to the resting potential. This can be seen in figure 1: when the membrane potential is clamped below the channel's resting potential (e.g. -60 mV), negative current flows (i.e. positive charge flows into the cell). However, when the membrane potential is set higher than the channel's resting potential (e.g. +60 mV), these channels pass very little charge out of the cell.

Simply put, this channel passes much more current in the inward direction than the outward one.

This current is caused by the interaction between electrical forces and diffusion (due to a difference in K⁺ ion concentrations on the inside and outside of the cell), as encapsulated by the Nernst equation.

Note that these channels are not perfect rectifiers, as they can pass some outward current in the voltage range up to about 30 mV above resting potential. It is thought that this current may play an important role in regulating the resting level of neuronal activity.

[edit] 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 in 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.

[edit] 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:

[edit] 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.

[edit] Diversity

[edit] 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).

[edit] See also

• Cardiac action potential
• G protein-coupled inwardly-rectifying potassium channel

[edit] External links

• MeSH Inward+Rectifier+Potassium+Channels
• UMich Orientation of Proteins in Membranes families/family-85 - Spatial positions of inward rectifier potassium channels in membranes

[edit] 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.