Inward

Inward-rectifier potassium ion channel

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. They are the targets of multiple toxins, and malfunction of the channels has been implicated in several diseases.

Overview of inward rectification

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.

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.

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:

Location	Function
cardiac myocytes	K_ir 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	K_ir channels are involved in regulation of nitric oxide synthase.
kidneys	K_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 (K_ir3) 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. Weaver mice have been examined in labs interested in neural development and disease for over 30 years.
pancreatic beta cells	K_ATP channels (comprised of K_ir6.2 and SUR1 subunits) control insulin release.

Biochemistry of K_ir channels

There are seven subfamilies of K_ir channels, denoted as K_ir1 - K_ir7. 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.

Diversity

Gene	Protein	Aliases	Associated subunits
	K_ir1.1	ROMK1	NHERF2
	K_ir2.1	IRK1	K_ir2.2, K_ir4.1, PSD-95, SAP97, AKAP79
	K_ir2.2	IRK2	K_ir2.1 and K_ir2.3 to form heteromeric channel, auxiliary subunit: SAP97, Veli-1, Veli-3, PSD-95
	K_ir2.3	IRK3	K_ir2.1 and K_ir2.3 to form heteromeric channel, PSD-95, Chapsyn-110/PSD-93
	K_ir2.4	IRK4	K_ir2.1 to form heteromeric channel
	K_ir3.1	GIRK1, KGA	K_ir3.2, K_ir3.4, K_ir3.5, K_ir3.1 is not functional by itself
	K_ir3.2	GIRK2	K_ir3.1, K_ir3.3, K_ir3.4 to form heteromeric channel
	K_ir3.3	GIRK3	K_ir3.1, K_ir3.2 to form heteromeric channel
	K_ir3.4	GIRK4	K_ir3.1, K_ir3.2, K_ir3.3
	K_ir4.1	K_ir1.2	K_ir4.2, K_ir5.1, and K_ir2.1 to form heteromeric channels
	K_ir4.2	K_ir1.3
	K_ir5.1	BIR 9
	K_ir6.1	K_ATP	SUR2B
	K_ir6.2	K_ATP	SUR1, SUR2A, and SUR2B
	K_ir7.1	K_ir1.4

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).