Inward-rectifier potassium ion channel

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]


Overview

Inwardly rectifing potassium channels (Kir, 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]

Definition of inward rectification

Figure 1. Whole-cell current recording of a Kir2 inwardly-rectifying potassium channel expressed in an HEK293 cell. There are 13 recordings 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.

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:

Location Function
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.[3] 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.[1] 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.

Diversity

Gene Protein Aliases Associated subunits
KCNJ1 Kir1.1 ROMK1 NHERF2
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
KCNJ15 Kir4.2 Kir1.3
KCNJ16 Kir5.1 BIR 9
KCNJ8 Kir6.1 KATP SUR2B
KCNJ11 Kir6.2 KATP SUR1, SUR2A, and SUR2B
KCNJ13 Kir7.1 Kir1.4

Diseases related to 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).

See also

External links

References

  1. 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. PMID 16382105. doi:10.1124/pr.57.4.11. 
  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. PMID 17093086. doi:10.1523/JNEUROSCI.3447-06.2006. 

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