Inward-rectifier potassium ion channel

Inward rectifier potassium channel

crystal structure of an inward rectifier potassium channel
Identifiers
Symbol IRK
Pfam PF01007
Pfam clan CL0030
InterPro IPR013521
SCOP 1n9p
SUPERFAMILY 1n9p
TCDB 1.A.2
OPM superfamily 8
OPM protein 3sya
Inward rectifier potassium channel N-terminal
Identifiers
Symbol IRK_N
Pfam PF08466
InterPro IPR013673

Inwardly rectifying potassium channels (Kir, IRK) are a specific subset of potassium (K+) selective ion channels. To date, seven subfamilies have been identified in various mammalian cell types,[1] plants,[2] and bacteria.[3] They are the targets of multiple toxins, and malfunction of the channels has been implicated in several diseases.[4] IRK channels possess a pore domain, homologous to that of voltage-gated ion channels, and flanking transmembrane segments (TMSs). They may exist in the membrane as homo- or heterooligomers and each monomer possesses between 2 and 4 TMSs. In terms of function, these proteins transport potassium (K+), with a greater tendency for K+ uptake than K+ export.[3]

Overview of inward rectification

Figure 1. Whole-cell current recordings of Kir2 inwardly-rectifying potassium channels expressed in an HEK293 cell. (This is a strongly inwardly rectifying current. Downward deflections are inward currents, upward deflections outward currents, and the x-axis is time in seconds.) There are 13 responses superimposed in this image. The bottom-most trace is current elicited by a voltage step to negative 60mV, and the top-most to positive 60mV, relative to the resting potential, which is close to the K+ reversal potential in this experimental system. Other traces are in 10mV increments between the two.

A channel that is "inwardly-rectifying" is one that passes current (positive charge) more easily in the inward direction (into the cell) than in the outward direction (out of the cell). It is thought that this current may play an important role in regulating neuronal activity, by helping to stabilize the resting membrane potential of the cell.

By convention, inward current is displayed in voltage clamp as a downward deflection, while an outward current (positive charge moving out of the cell) is shown as an upward deflection. At membrane potentials negative to potassium's reversal potential, inwardly rectifying K+ channels support the flow of positively charged K+ ions 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 negative to the channel's resting potential (e.g. -60 mV), inward current flows (i.e. positive charge flows into the cell). However, when the membrane potential is set positive to 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. 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.

These channels differ from the potassium channels that are typically responsible for repolarizing a cell following an action potential, such as the delayed rectifier and A-type potassium channels. Those more "typical" potassium channels preferentially carry outward (rather than inward) potassium currents at depolarized membrane potentials, and may be thought of as "outwardly rectifying." When first discovered, inward rectification was named "anomalous rectification" to distinguish it from outward potassium currents.[5]

Inward rectifiers also differ from tandem pore domain potassium channels, which are largely responsible for "leak" K+ currents.[6] Some inward rectifiers, termed "weak inward rectifiers", carry measurable outward K+ currents at voltages positive to the K+ reversal potential (corresponding to, but larger than, the small currents above the 0 nA line in figure 1). They, along with the "leak" channels, establish the resting membrane potential of the cell. Other inwardly rectifying channels, termed "strong inward rectifiers," carry very little outward current at all, and are mainly active at voltages negative to the reversal potential, where they carry inward current (the much larger currents below the 0 nA line in figure 1).[7]

Mechanism of inward rectification

The phenomenon of inward rectification of Kir channels is the result of high-affinity block by endogenous polyamines, namely spermine, as well as magnesium ions, that plug the channel pore at positive potentials, resulting in a decrease in outward currents. This voltage-dependent block by polyamines results in efficient conduction of current only in the inward direction. While the principal idea of polyamine block is understood, the specific mechanisms are still controversial.[8]

Activation by PIP2

All Kir channels require phosphatidylinositol 4,5-bisphosphate (PIP2) for activation.[9] PIP2 binds to and directly activates Kir 2.2 with agonist-like properties.[10] In this regard Kir channels are PIP2 ligand-gated ion channels.

Role of Kir channels

Kir channels are found in multiple cell types, including macrophages, cardiac and kidney cells, leukocytes, neurons, and endothelial cells. By mediating a small depolarizing K+ current at negative membrane potentials, they help establish resting membrane potential, and in the case of the Kir3 group, they help mediate inhibitory neurotransmitter responses, but 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 cardiac action potential. This type of inward-rectifier channel is distinct from delayed rectifier K+ channels, which help repolarize 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, modulated by neurotransmitters. 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.[11] Relative to non-ataxic controls, Weaver mutants have deficits in motor coordination and changes in regional brain metabolism.[12] Weaver mice have been examined in labs interested in neural development and disease for over 30 years.
pancreatic beta cells KATP channels (composed of Kir6.2 and SUR1 subunits) control insulin release.

Regulation

Voltage-dependence may be regulated by external K+, by internal Mg2+, by internal ATP and/or by G-proteins. The P domains of IRK channels exhibit limited sequence similarity to those of the VIC family. Inward rectifiers play a role in setting cellular membrane potentials, and closing of these channels upon depolarization permits the occurrence of long duration action potentials with a plateau phase. Inward rectifiers lack the intrinsic voltage sensing helices found in many VIC family channels. In a few cases, those of Kir1.1a, Kir6.1 and Kir6.2, for example, direct interaction with a member of the ABC superfamily has been proposed to confer unique functional and regulatory properties to the heteromeric complex, including sensitivity to ATP. These ATP-sensitive channels are found in many body tissues. They render channel activity responsive to the cytoplasmic ATP/ADP ratio (increased ATP/ADP closes the channel). The human SUR1 and SUR2 sulfonylurea receptors (spQ09428 and Q15527, respectively) are the ABC proteins that regulate both the Kir6.1 and Kir6.2 channels in response to ATP, and CFTR (TC #3.A.1.208.4) may regulate Kir1.1a.[13]

Structure

The crystal structure[14] and function[15] of bacterial members of the IRK-C family have been determined. KirBac1.1, from Burkholderia pseudomallei, is 333 amino acyl residues (aas) long with two N-terminal TMSs flanking a P-loop (residues 1-150), and the C-terminal half of the protein is hydrophilic. It transports monovalent cations with the selectivity: K ~ Rb ~ Cs >> Li ~ Na ~ NMGM (protonated N-methyl-D-glucamine). Activity is inhibited by Ba2+, Ca2+, and low pH.[15]

Classification 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 (i.e. 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

See also

References

  1. 1 2 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". Pharmacological Reviews 57 (4): 509–26. doi:10.1124/pr.57.4.11. PMID 16382105.
  2. ↑ Hedrich R, Moran O, Conti F, Busch H, Becker D, Gambale F, Dreyer I, Küch A, Neuwinger K, Palme K (1995). "Inward rectifier potassium channels in plants differ from their animal counterparts in response to voltage and channel modulators". Eur. Biophys. J. 24 (2): 107–15. doi:10.1007/BF00211406. PMID 8582318.
  3. 1 2 "1.A.2 Inward Rectifier K Channel (IRK-C) Family". TCDB. Retrieved 2016-04-09.
  4. ↑ Abraham MR, Jahangir A, Alekseev AE, Terzic A (1999). "Channelopathies of inwardly rectifying potassium channels". FASEB J 13 (14): 1901–10. PMID 10544173.
  5. ↑ Bertil Hille (2001). Ion Channels of Excitable Membranes 3rd ed. (Sinauer: Sunderland, MA), p. 151. ISBN 0-87893-321-2.
  6. ↑ Hille, p. 155.
  7. ↑ Hille, p. 153.
  8. ↑ "The mechanism of inward rectification of potassium channels: "long-pore plugging" by cytoplasmic polyamines". The Journal of General Physiology 106 (5): 923–955. 1995-11-01. ISSN 0022-1295. PMC 2229292. PMID 8648298.
  9. ↑ Tucker SJ, Baukrowitz T (2008). "How highly charged anionic lipids bind and regulate ion channels". J. Gen. Physiol. 131 (5): 431–8. doi:10.1085/jgp.200709936. PMC 2346576. PMID 18411329.
  10. ↑ Hansen SB, Tao X, MacKinnon R (2011). "Structural basis of PIP2 activation of the classical inward rectifier K+ channel Kir2.2.". Nature 477 (7365): 495–498. doi:10.1038/nature10370. PMC 3324908. PMID 21874019.
  11. ↑ Peng J, Xie L, Stevenson FF, Melov S, Di Monte DA, Andersen JK (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.
  12. ↑ Strazielle C, Deiss V, Naudon L, Raisman-Vozari R, Lalonde R (2006). "Regional brain variations of cytochrome oxidase activity and motor coordination in Girk2(Wv) (Weaver) mutant mice.". Neuroscience 142 (2): 437–49. doi:10.1016/j.neuroscience.2006.06.011. PMID 16844307.
  13. ↑ Wei, Ming-Hui; Chaturvedi, Kabir; Guegler, Karl; Webster, Marion; Ketchum, Karen A.; Di, Francesco Valentina; BEASLEY, Ellen § (Nov 29, 2001), Isolated human transporter proteins, nucleic acid molecules encoding human transporter proteins, and uses thereof, retrieved 2016-04-09
  14. ↑ Kuo, Anling; Gulbis, Jacqueline M.; Antcliff, Jennifer F.; Rahman, Tahmina; Lowe, Edward D.; Zimmer, Jochen; Cuthbertson, Jonathan; Ashcroft, Frances M.; Ezaki, Takayuki (2003-06-20). "Crystal structure of the potassium channel KirBac1.1 in the closed state". Science (New York, N.Y.) 300 (5627): 1922–1926. doi:10.1126/science.1085028. ISSN 1095-9203. PMID 12738871.
  15. 1 2 Enkvetchakul, Decha; Bhattacharyya, Jaya; Jeliazkova, Iana; Groesbeck, Darcy K.; Cukras, Catherine A.; Nichols, Colin G. (2004-11-05). "Functional characterization of a prokaryotic Kir channel". The Journal of Biological Chemistry 279 (45): 47076–47080. doi:10.1074/jbc.C400417200. ISSN 0021-9258. PMID 15448150.
  16. ↑ Ryan DP, da Silva MR, Soong TW, Fontaine B, Donaldson MR, Kung AW, Jongjaroenprasert W, Liang MC, Khoo DH, Cheah JS, Ho SC, Bernstein HS, Maciel RM, Brown RH, Ptácek LJ (2010). "Mutations in Potassium Channel Kir2.6 Cause Susceptibility to Thyrotoxic Hypokalemic Periodic Paralysis". Cell 140 (1): 88–98. doi:10.1016/j.cell.2009.12.024. PMC 2885139. PMID 20074522.

Further reading

Bertil Hille (2001). Ion Channels of Excitable Membranes 3rd ed. (Sinauer: Sunderland, MA), pp. 149–154. ISBN 0-87893-321-2.

External links

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