Inward-rectifier potassium channel
Inward rectifier potassium channel | |||||||||
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TCDB 1.A.2 | | ||||||||
OPM superfamily | 8 | ||||||||
OPM protein | 3SPG | ||||||||
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Inward-rectifier potassium channels (Kir, IRK) are a specific
Overview of inward rectification
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
By convention, inward current (positive charge moving into the cell) 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 current. Simply put, this channel passes much more current in the inward direction than the outward one, at its operating voltage range. 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.[8]
Inward rectifiers also differ from
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.[11]
Activation by PIP2
All Kir channels require
Role
Kir channels are found in multiple cell types, including
Location | Function |
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cardiac myocytes |
Kir channels close upon depolarization, slowing membrane repolarization and helping maintain a more prolonged potassium leak channels, which provide much of the basis for the resting membrane potential .
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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.[14] Relative to non-ataxic controls, Weaver mutants have deficits in motor coordination and changes in regional brain metabolism.[15] Weaver mice have been examined in labs interested in neural development and disease for over 30 years.
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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.[16]
Structure
The crystal structure[17] and function[18] 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.[18]
Classification
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
Diversity
Gene | Protein | Aliases | Associated subunits |
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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 |
- 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.
- low levels of potassiumin the body.
- KCNJ2)
- Barium poisoningis likely due to its ability to block 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).
- Thyrotoxic hypokalaemic periodic paralysis has been linked to altered Kir2.6 function.[19]
- EAST/SeSAME syndrome is caused by mutations in KCNJ10.[20]
See also
- G protein-coupled inwardly-rectifying potassium channel
- hERG
- Transporter Classification Database
References
- ^ S2CID 11588492.
- S2CID 12718513.
- ^ a b "1.A.2 Inward Rectifier K Channel (IRK-C) Family". TCDB. Retrieved 2016-04-09.
- PMID 25633344.
- S2CID 22205168.
- ISSN 0095-9898.
- PMID 5499788.
- ISBN 0-87893-321-2.
- ^ Hille, p. 155.
- ^ Hille, p. 153.
- PMID 8648298.
- PMID 18411329.
- PMID 21874019.
- PMID 17093086.
- S2CID 33064439.
- ^ WO application 0190360, Wei MH, Chaturvedi K, Guegler K, Webster M, Ketchum KA, Di Francesco V, Beasley E, "Isolated human transporter proteins, nucleic acid molecules encoding human transporter proteins, and uses thereof", published 29 November 2001, assigned to Apperla Corporation
- S2CID 2703162.
- ^ PMID 15448150.
- PMID 20074522.
- PMID 19420365.
Further reading
- ISBN 0-87893-321-2.
External links
- Inward+Rectifier+Potassium+Channels at the U.S. National Library of Medicine Medical Subject Headings (MeSH).
- "Inwardly Recifying Potassium Channels". IUPHAR Database of Receptors and Ion Channels. International Union of Basic and Clinical Pharmacology.
- UMich Orientation of Proteins in Membranes families/family-85 - Spatial positions of inward rectifier potassium channels in membranes.