Inward-rectifier potassium ion channel
Encyclopedia
Inwardly rectifying potassium channels (Kir, IRK) are a specific subset of potassium selective ion channels
. To date, seven subfamilies have been identified in various mammalian cell types. They are the targets of multiple toxins, and malfunction of the channels has been implicated in several diseases.
A channel that is "inwardly-rectifying" is one that passes current (positive charge) more easily in the inward direction (into the cell). It is thought that this current may play an important role in regulating neuronal activity, by helping to establish 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.
Inward rectifiers also differ from tandem pore domain potassium channel
s, which are largely responsible for "leak" K+ currents. 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).
s, 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 causes currents to be conducted well only in the inward direction. While the principal idea of polyamine block is understood, the specific mechanisms are still controversial.
cells, leukocytes, neurons, and endothelial cells. By mediating a small hyperpolarizing
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:
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.
(2001). Ion Channels of Excitable Membranes 3rd ed. (Sinauer: Sunderland, MA), pp. 149–154. ISBN 0878933212.
Potassium channel
In the field of cell biology, potassium channels are the most widely distributed type of ion channel and are found in virtually all living organisms. They form potassium-selective pores that span cell membranes...
. To date, seven subfamilies have been identified in various mammalian cell types. They are the targets of multiple toxins, and malfunction of the channels has been implicated in several diseases.
Overview of inward rectification
By convention, inward current is displayed in voltage clamp
Voltage clamp
The voltage clamp is used by electrophysiologists to measure the ion currents across the membrane of excitable cells, such as neurons, while holding the membrane voltage at a set level. Cell membranes of excitable cells contain many different kinds of ion channels, some of which are voltage gated...
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
Reversal potential
In a biological membrane, the reversal potential of an ion is the membrane potential at which there is no net flow of that particular ion from one side of the membrane to the other...
, 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
Action potential
In physiology, an action potential is a short-lasting event in which the electrical membrane potential of a cell rapidly rises and falls, following a consistent trajectory. Action potentials occur in several types of animal cells, called excitable cells, which include neurons, muscle cells, and...
, 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.
Inward rectifiers also differ from tandem pore domain potassium channel
Tandem pore domain potassium channel
The two-pore-domain potassium channel is a family of 15 members form what is known as "leak channels" which possess Goldman-Hodgkin-Katz rectification. These channels are regulated by several mechanisms including oxygen tension, pH, mechanical stretch, and G-proteins...
s, which are largely responsible for "leak" K+ currents. 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).
Mechanism of inward rectification
The phenomenon of inward rectification of Kir channels is the result of high-affinity block by endogenous polyaminePolyamine
A polyamine is an organic compound having two or more primary amino groups .This class of compounds includes several synthetic substances that are important feedstocks for the chemical industry, such as ethylene diamine , 1,3-diaminopropane , and hexamethylenediamine...
s, namely spermine
Spermine
Spermine is a polyamine involved in cellular metabolism found in all eukaryotic cells. Formed from spermidine, it is found in a wide variety of organisms and tissues and is an essential growth factor in some bacteria. It is found as a polycation at physiological pH...
, as well as magnesium
Magnesium
Magnesium is a chemical element with the symbol Mg, atomic number 12, and common oxidation number +2. It is an alkaline earth metal and the eighth most abundant element in the Earth's crust and ninth in the known universe as a whole...
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 only in the inward direction. While the principal idea of polyamine block is understood, the specific mechanisms are still controversial.
Role of Kir channels
Kir channels are found in multiple cell types, including macrophages, cardiac and kidneyKidney
The kidneys, organs with several functions, serve essential regulatory roles in most animals, including vertebrates and some invertebrates. They are essential in the urinary system and also serve homeostatic functions such as the regulation of electrolytes, maintenance of acid–base balance, and...
cells, leukocytes, neurons, and endothelial cells. By mediating a small hyperpolarizing
Hyperpolarization
Hyperpolarization has several meanings:* Hyperpolarization occurs when the strength of the electric field across the width of a cell membrane increases...
K+ current at negative membrane potentials, they help establish resting membrane potential, and in the case of the Kir3
G protein-coupled inwardly-rectifying potassium channel
The G protein-coupled inwardly-rectifying potassium channels are a family of inward-rectifier potassium ion channels which are activated via a signal transduction cascade starting with ligand-stimulated G protein-coupled receptors . GPCRs in turn release activated G-protein βγ- subunits from...
group, they help mediate inhibitory neurotransmitter
Neurotransmitter
Neurotransmitters are endogenous chemicals that transmit signals from a neuron to a target cell across a synapse. Neurotransmitters are packaged into synaptic vesicles clustered beneath the membrane on the presynaptic side of a synapse, and are released into the synaptic cleft, where they bind to...
responses, but their roles in cellular physiology vary across cell types:
| Location | Function >- | cardiac myocytes |
ir channels close upon depolarization, slowing membrane repolarization and helping maintain a more prolonged cardiac action potential Cardiac action potential In electrocardiography, the cardiac action potential is a specialized action potential in the heart, necessary for the electrical conduction system of the heart.... . This type of inward-rectifier channel is distinct from delayed rectifier K+ channels Voltage-gated potassium channel Voltage-gated potassium channels are transmembrane channels specific for potassium and sensitive to voltage changes in the cell's membrane potential. During action potentials, they play a crucial role in returning the depolarized cell to a resting state.... , which help repolarize nerve and muscle cells after action potential Action potential In physiology, an action potential is a short-lasting event in which the electrical membrane potential of a cell rapidly rises and falls, following a consistent trajectory. Action potentials occur in several types of animal cells, called excitable cells, which include neurons, muscle cells, and... s; and potassium leak channels Tandem pore domain potassium channel The two-pore-domain potassium channel is a family of 15 members form what is known as "leak channels" which possess Goldman-Hodgkin-Katz rectification. These channels are regulated by several mechanisms including oxygen tension, pH, mechanical stretch, and G-proteins... , which provide much of the basis for the resting membrane potential Resting potential The relatively static membrane potential of quiescent cells is called the resting membrane potential , as opposed to the specific dynamic electrochemical phenomena called action potential and graded membrane potential.... . >- | endothelial cells |
ir channels are involved in regulation of nitric oxide synthase Nitric oxide synthase Nitric oxide synthases are a family of enzymes that catalyze the production of nitric oxide from L-arginine. NO is an important cellular signaling molecule, having a vital role in many biological processes... . >- | kidneys |
ir 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) G protein-coupled inwardly-rectifying potassium channel The G protein-coupled inwardly-rectifying potassium channels are a family of inward-rectifier potassium ion channels which are activated via a signal transduction cascade starting with ligand-stimulated G protein-coupled receptors . GPCRs in turn release activated G-protein βγ- subunits from... are important regulators, modulated by neurotransmitters. A mutation in the GIRK2 KCNJ6 G protein-activated inward rectifier potassium channel 2 is a protein that in humans is encoded by the KCNJ6 gene.-Interactions:KCNJ6 has been shown to interact with KCNJ9 and DLG1.-See also:* G protein-coupled inwardly-rectifying potassium channel... channel leads to the weaver mouse mutation. "Weaver" mutant mice are ataxic and display a neuroinflammation-mediated degeneration of their dopaminergic neurons. Relative to non-ataxic controls, Weaver mutants have deficits in motor coordination and changes in regional brain metabolism. Weaver mice have been examined in labs interested in neural development and disease for over 30 years. >- | pancreatic beta cell Beta cell Beta cells are a type of cell in the pancreas located in the so-called islets of Langerhans. They make up 65-80% of the cells in the islets.-Function:... s |
KATP channels (composed of Kir6.2 Kir6.2 Kir6.2 is a major subunit of the ATP-sensitive K+ channel, an inward-rectifier potassium ion channel. The gene encoding the channel is called KCNJ11 and mutations in this gene are associated with congenital hyperinsulinism.-Structure:... and SUR1 Sulfonylurea receptor In the field of molecular biology, the sulfonylurea receptors are membrane proteins which are the molecular targets of the sulfonylurea class of antidiabetic drugs whose mechanism of action is to promote insulin release from pancreatic beta cells. More specifically, SUR proteins are subunits of... subunits) control insulin release. |
Biochemistry of Kir channels
There are seven subfamilies of Kir channels, denoted as Kir1 - Kir7. 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
Alpha helix
A common motif in the secondary structure of proteins, the alpha helix is a right-handed coiled or spiral conformation, in which every backbone N-H group donates a hydrogen bond to the backbone C=O group of the amino acid four residues earlier...
(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 >- | |
Kir1.1 ROMK ROMK is an acronym for the Renal Outer Medullary Potassium channel. This is an ATP-dependent potassium channel that transports potassium out of cells. It plays an important role in potassium recycling in the thick ascending limb and potassium secretion in the cortical collecting duct of the... |
ROMK1 | NHERF2 Sodium-hydrogen exchange regulatory cofactor 2 Sodium-hydrogen exchange regulatory cofactor NHE-RF2 also known as tyrosine kinase activator protein 1 or SRY-interacting protein 1 is a protein that in humans is encoded by the SLC9A3R2 gene.NHERF-2) is a scaffold protein that connects plasma membrane proteins with members of the... >- | |
Kir2.1 KCNJ2 The Kir2.1 inward-rectifier potassium ion channel is encoded by the gene.- Clinical significance :A defect in this gene is associated with Andersen-Tawil syndrome.A mutation in the KCNJ2 gene has also been shown to cause short QT syndrome.... |
IRK1 | ir2.2, Kir4.1, PSD-95 DLG4 PSD-95 also known as SAP-90 is a protein that in humans is encoded by the DLG4 gene.... , SAP97 DLG1 Disks large homolog 1 , also known as synapse-associated protein 97 or SAP97, is a protein that in humans is encoded by the SAP97 gene.... , AKAP79 AKAP5 A-kinase anchor protein 5 is an enzyme that in humans is encoded by the AKAP5 gene.-Interactions:AKAP5 has been shown to interact with Calcineurin and GABRB3.-Further reading:... >- | |
Kir2.2 KCNJ12 ATP-sensitive inward rectifier potassium channel 12 is a protein that in humans is encoded by the KCNJ12 gene.-Interactions:KCNJ12 has been shown to interact with LIN7C, DLG4, LIN7B, DLG2, DLG3, DLG1, APBA1, LIN7A and CASK.- External links :... |
IRK2 | ir2.1 and Kir2.3 to form heteromeric channel, auxiliary subunit: SAP97, Veli-1 LIN7A Lin-7 homolog A is a protein that in humans is encoded by the LIN7A gene.-Interactions:LIN7A has been shown to interact with KCNJ12, DLG1 and CASK.-Further reading:... , Veli-3 LIN7C Lin-7 homolog C is a protein that in humans is encoded by the LIN7C gene.-Interactions:LIN7C has been shown to interact with KCNJ4, KCNJ12 and DLG1.-Further reading:... , PSD-95 >- | |
Kir2.3 KCNJ4 Potassium inwardly-rectifying channel, subfamily J, member 4, also known as KCNJ4 or Kir2.3, is a human gene.-Interactions:KCNJ4 has been shown to interact with LIN7C, LIN7B, DLG4, DLG1 and CASK.... |
IRK3 | ir2.1 and Kir2.3 to form heteromeric channel, PSD-95, Chapsyn-110 DLG2 Disks large homolog 2 also known as channel-associated protein of synapse-110 or postsynaptic density protein 93 is a protein that in humans is encoded by the DLG2 gene.- Function :... /PSD-93 >- | |
Kir2.4 KCNJ14 Potassium inwardly-rectifying channel, subfamily J, member 14 , also known as Kir2.4, is a human gene.... |
IRK4 | ir2.1 to form heteromeric channel >- | |
Kir3.1 KCNJ3 Potassium inwardly-rectifying channel, subfamily J, member 3, also known as KCNJ3 or Kir3.1, is a human gene.-See also:* G protein-coupled inwardly-rectifying potassium channel* Inward-rectifier potassium ion channel- External links :... |
GIRK1, KGA | ir3.2, Kir3.4, Kir3.5, Kir3.1 is not functional by itself >- | |
Kir3.2 KCNJ6 G protein-activated inward rectifier potassium channel 2 is a protein that in humans is encoded by the KCNJ6 gene.-Interactions:KCNJ6 has been shown to interact with KCNJ9 and DLG1.-See also:* G protein-coupled inwardly-rectifying potassium channel... |
GIRK2 | ir3.1, Kir3.3, Kir3.4 to form heteromeric channel >- | |
Kir3.3 KCNJ9 G protein-activated inward rectifier potassium channel 3 is a protein that in humans is encoded by the KCNJ9 gene.-See also:* G protein-coupled inwardly-rectifying potassium channel* Inward-rectifier potassium ion channel... |
GIRK3 | ir3.1, Kir3.2 to form heteromeric channel >- | |
Kir3.4 KCNJ5 G protein-activated inward rectifier potassium channel 4 is a protein that in humans is encoded by the KCNJ5 gene and is a type of G protein-gated ion channel.-See also:* G protein-coupled inwardly-rectifying potassium channel... |
GIRK4 | ir3.1, Kir3.2, Kir3.3 >- | |
Kir4.1 KCNJ10 ATP-sensitive inward rectifier potassium channel 10 is a protein that in humans is encoded by the KCNJ10 gene.-SeSAME syndrome:Humans with mutations in the KCNJ10 gene that cause loss of function in related K+ channels can display seizures, sensorineural deafness, ataxia, mental retardation, and... |
Kir1.2 | ir4.2, Kir5.1, and Kir2.1 to form heteromeric channels >- | |
Kir4.2 KCNJ15 Potassium inwardly-rectifying channel, subfamily J, member 15, also known as KCNJ15 is a human gene, which encodes the Kir4.2 protein.- Function :... |
Kir1.3 | >- | Kir5.1 KCNJ16 Potassium inwardly-rectifying channel, subfamily J, member 16 is a human gene encoding the Kir5.1 protein.-Further reading:... |
BIR 9 | >- | Kir6.1 KCNJ8 Potassium inwardly-rectifying channel, subfamily J, member 8, also known as KCNJ8, is a human gene encoding the Kir6.1 protein.. A mutation in KCNJ8 has been associated with cardiac arrest in the early repolarization syndrome.... |
KATP | SUR2B ABCC9 ATP-binding cassette, sub-family C member 9 also known as sulfonylurea receptor 2 is a ATP-binding cassette transporter that in humans is encoded by the ABCC9 gene.- Function :... >- | |
Kir6.2 Kir6.2 Kir6.2 is a major subunit of the ATP-sensitive K+ channel, an inward-rectifier potassium ion channel. The gene encoding the channel is called KCNJ11 and mutations in this gene are associated with congenital hyperinsulinism.-Structure:... |
KATP | SUR1 ABCC8 ATP-binding cassette transporter sub-family C member 8 is a protein that in humans is encoded by the ABCC8 gene. ABCC8 orthologs have been identified in all mammals for which complete genome data are available.-External links:* *... , SUR2A ABCC9 ATP-binding cassette, sub-family C member 9 also known as sulfonylurea receptor 2 is a ATP-binding cassette transporter that in humans is encoded by the ABCC9 gene.- Function :... , and SUR2B ABCC9 ATP-binding cassette, sub-family C member 9 also known as sulfonylurea receptor 2 is a ATP-binding cassette transporter that in humans is encoded by the ABCC9 gene.- Function :... >- | |
Kir7.1 KCNJ13 Potassium inwardly-rectifying channel, subfamily J, member 13 is a human gene encoding the Kir7.1 protein.... |
Kir1.4 |
Diseases related to Kir channels
- 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 hypoglycemiaHypoglycemiaHypoglycemia or hypoglycæmia is the medical term for a state produced by a lower than normal level of blood glucose. The term literally means "under-sweet blood"...
. - Bartter's syndrome can be caused by mutations in Kir 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 Kir2.1. Depending on the mutation, it can be dominant or recessive. It is characterized by periodic paralysisPeriodic paralysisPeriodic paralysis is a group of rare genetic diseases that lead to weakness or paralysis from common triggers such as cold, heat, high carbohydrate meals, not eating, stress or excitement and physical activity of any kind...
, cardiac arrhythmias and dysmorphic features. (See also KCNJ2KCNJ2The Kir2.1 inward-rectifier potassium ion channel is encoded by the gene.- Clinical significance :A defect in this gene is associated with Andersen-Tawil syndrome.A mutation in the KCNJ2 gene has also been shown to cause short QT syndrome....
) - Barium poisoning is likely due to its ability to block Kir channels.
- AtherosclerosisAtherosclerosisAtherosclerosis is a condition in which an artery wall thickens as a result of the accumulation of fatty materials such as cholesterol...
(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.
See also
- Potassium channelPotassium channelIn the field of cell biology, potassium channels are the most widely distributed type of ion channel and are found in virtually all living organisms. They form potassium-selective pores that span cell membranes...
- G protein-coupled inwardly-rectifying potassium channelG protein-coupled inwardly-rectifying potassium channelThe G protein-coupled inwardly-rectifying potassium channels are a family of inward-rectifier potassium ion channels which are activated via a signal transduction cascade starting with ligand-stimulated G protein-coupled receptors . GPCRs in turn release activated G-protein βγ- subunits from...
Further reading
Bertil HilleBertil Hille
Bertil Hille is a professor in the Department of Physiology and Biophysics at the University of Washington. He is particularly well known for his research and expertise on cell signalling by ion channels.-Early life and education:...
(2001). Ion Channels of Excitable Membranes 3rd ed. (Sinauer: Sunderland, MA), pp. 149–154. ISBN 0878933212.