Inward rectifier potassium channels, or Kir Channels: a class of potassium channels generated by the tetrameric arrangement of one-pore/two-transmembrane helix (1P/2TM) protein subunits, often associated with additional b subunits. As potassium channels, they serve to modulate cell excitability , being involved in repolarization of action potentials (Fig), setting the resting potential (Fig) of the cell, and contributing to potassium homeostasis.

Inward Rectification: decreased conductance upon depolarization. In classical inward rectifiers, rectification is "strong" and currents rapidly decline at voltages positive to the reversal potential. In other Kir channels, rectification is "weak" and currents decline only gradually at voltages positive to the reversal potential. 

Molecular Basis and Functional Diversity of Kir Channels: Seven sub-families of Kir channels are known each sharing ~60% amino acid identity between individual members within each sub family and ~40% identity between subfamilies.

Diversity of Kir Channels

Molecular Structure of Kir Channels: All Kir channels are tetrameric proteins of one-pore/two-transmembrane (1P/2TM) domain subunits that equally contribute to the formation of highly selective K channels. Most Kir channels can be assembled in functional homotetramers while some require heteromeric assembly (Fig). For example, functional GIRK channels underlying IK_ACh current in atria are heteromultimers of two members of Kir3 subfamily: Kir3.1 and Kir3.4.
    The crystal structures of a number of bacterial potassium channels has been recently obtained.

 The Mechanism of Strong Inward Rectification: Inward, or ‘anomalous’, rectification of potassium permeability refers to increases of potassium conductance under hyperpolarization and decreases under depolarization, the effect opposite to that of ‘normal’ outward or delayed rectification that is seen in voltage gated potassium channels. Classical inward rectification is so strong that only small currents can be measured in the outward direction at voltages positive to the K⁺ reversal potential (EK) while large inward currents can be easily observed negative to it. This strongly voltage-dependent rectification also strongly depends on the concentration of external K⁺ ([KOUT]), such that increasing KOUT relieves the rectification, so that the mid-point voltage of rectification shifts nearly perfectly with corresponding change in EK. It is now established that strong inward rectification results primarily from voltage-dependent block by intracellular organic cations called polyamines. Of the polyamines, spermine and spermidine are the most potent inducers of rectification although contributions of putrescine and of Mg²⁺ ions are also important.

Both the steady state and the kinetic properties of rectification result from the combined action of polyamines and Mg²⁺ ions. Micromolar concentrations of spermine and spermidine are required to reproduce the degree of rectification observed in native cells. With exogenously expressed Kir channels at physiologically relevant membrane potentials, total cellular polyamine levels (10–10,000 mM) are clearly sufficient to cause appropriate rectification.

The degree of rectification varies greatly among members of the Kir superfamily and is critical to their respective functional roles. Kir2 and Kir3 encode classical "strong" inward rectifier channels, while other members encode channels with variably "milder" or "weaker" rectification. For example, because of mild rectification of the KATP channel its activation causes considerable shortening of cardiac action potential, thus reducing entry of Ca²⁺ through voltage-dependent Ca²⁺ channels and hence conserving ATP under conditions of metabolic stress. Conversely, the strong inward rectification of Kir2.1 channels underlying IK1 current in the heart results in very small currents flowing through these channels during depolarization phase of action potential while increased conductance around resting potential leads to its stabilization.

The Mechanism of Strong Inward Rectification

Channelopathies Resulting from Kir Channel Mutations: 
    Several chanelopathies resulting from mutations in Kir channels are known.

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Last updated: July 12, 2003.